E-isomeric fullerene derivatives

ABSTRACT

An E-isomeric fulleropyrrolidine compound of formula (I):is disclosed. Also disclosed is a method for preparing and polymers prepared from such a compound.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 08/976,532,filed Nov. 20, 1997 now U.S. Pat. No. 6,046,361, which, in turn, is acontinuation-in-part of U.S. Ser. No. 8/893,055, filed Jul. 15, 1997,now abandoned which, in turn, is a continuation-in-part of U.S. Ser. No.08/547,714, filed Oct. 26, 1995, now U.S. Pat. No. 5,648,523.

BACKGROUND OF THE INVENTION

Cancer remains a formidable disease with a high mortality rate intoday's society. Indeed, cancer is second only to cardiovascular diseaseas a cause of death, killing one out of four people in developedcountries.

Cancerous tumors commonly originate from normal cells which transforminto malignant cells or tumors. The initial tumor growth may be slow andthus may be difficult to detect. The growth often becomes moreaggressive and invasive with time, eventually spreading throughout thewhole body and resulting in death.

Photodynamic therapy (PDT) is one of the methods for treating tumors.For review, see Dougherty, T. J. Photochem. Photobiol. 1993, 58, 895. Atpresent, the most commonly used sensitizers for clinical PDT practicesare Photofrin II, an enriched active fraction of hematoporphyrinderivatives, and disulfonated aluminum phthalocyanine. These compounds,once photoactivated, induce severe oxidative damage to the structure oflipids, proteins, and nucleic acids. Since many biologically activemolecules, e.g., DNA, demonstrate higher affinity toward stereospecificligands, it is therefore desirable to develop stereospecific PDTsensitizers to enhance cytotoxicity of such antitumor agents.

SUMMARY

An aspect of this invention relates to a compound of formula (I):

F_(f) is F(—K)_(m)(—Y—Z)_(q). F is a fullerene core. Each K,independently, is —OH, —SH, —NH₂, —NHOH, —SO₃H, —OSO₃H, —CO₂H, —CONH₂,—CONHNH₂, —P(OH)₃, —PO(OH)₂, —O—PO(OH)₂, —O—PO(OH)—O—PO(OH)₂,—O—PO(O⁻)—O—CH₂CH₂—NH₃ ⁺, —O—PO(O⁻)—O—CH₂CH₂—N⁺(CH₃)₃, -glycoside,—OCH₃, —OCH₂(CHOH)₄—CH₂OH, —OCH₂(CHOH)₂—CH₂OH, —NH—CH₂—CO₂H,—[CH(CO₂H)—CH₂]₁₋₁₀₀—OH, —[CH(CO₂R^(a))—CH₂]₁₋₁₀₀—OH,—[C(CH₃)(CO₂H)—CH₂]₁₋₁₀₀—OH, —[C(CH₃)(CO₂R^(a))—CH₂]₁₋₁₀₀—OH, —N(OH)₂,—NH₃ ⁺, —N⁺H₂R^(a), —N⁺HR^(a)R^(b), or —N⁺R^(a)R^(b)R^(c). Each Y is—A—B—, in which A is —O—, —NH—, —S—, —CO—O—, —O—CO—, —O—CO—O—,—O—CO—NH—, —NH—CO—NH—, —CO—NH—, or —NH—CO; and B is—R^(a)—O—[Si(CH₃)₂—O—]₁₋₁₀₀, C₁₋₂₀₀₀ alkyl, C₆₋₄₀ aryl, C₇₋₂₀₀₀alkylaryl, C₇₋₂₀₀₀ arylalkyl, (C₁₋₃₀ alkyl ether)₁₋₁₀₀, (C₆₋₄₀ arylether)₁₋₁₀₀, (C₇₋₂₀₀₀ alkaryl ether)₁₋₁₀₀, (C₇₋₂₀₀₀ arylalkylether)₁₋₁₀₀, (C₁₋₃₀ alkyl thioether)₁₋₁₀₀, (C₆₋₄₀ aryl thioether)₁₋₁₀₀,(C₇₋₂₀₀₀ alkylaryl thioether)₁₋₁₀₀, (C₇₋₂₀₀₀ arylalkyl thioether)₁₋₁₀₀,(C₂₋₅₀ alkyl ester)₁₋₁₀₀, (C₇₋₂₀₀₀ aryl ester)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylarylester)₁₋₁₀₀, (C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀, —R^(a)—CO—O—(C₁₋₃₀ alkylether)₁₋₁₀₀, —R^(a)—CO—O—(C₆₋₄₀ aryl ether)₁₋₁₀₀, —R^(a)—CO—O—(C₇₋₂₀₀₀alkylaryl ether)₁₋₁₀₀, —R^(a)—CO—O—(C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀,(C₄₋₅₀ alkyl urethane)₁₋₁₀₀, (C₁₄₋₆₀ aryl urethane)₁₋₁₀₀, (C₁₀₋₂₀₀₀alkylaryl urethane)₁₋₁₀₀, (C₁₀₋₂₀₀₀ arylalkyl urethane)₁₋₁₀₀, (C₅₋₅₀alkyl urea)₁₋₁₀₀, (C₁₄₋₆₀ aryl urea)₁₋₁₀₀, (C₁₀₋₂₀₀₀ alkylarylurea)₁₋₁₀₀, (C₁₀₋₂₀₀₀ arylalkyl urea)₁₋₁₀₀, (C₂₋₅₀ alkyl amide)₁₋₁₀₀,(C₇₋₆₀ aryl amide)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylaryl amide)₁₋₁₀₀, (C₈₋₂₀₀₀arylalkyl amide)₁₋₁₀₀, (C₃₋₃₀ alkyl anhydride)₁₋₁₀₀, (C₈₋₅₀ arylanhydride)₁₋₁₀₀, (C₉₋₂₀₀₀ alkylaryl anhydride)₁₋₁₀₀, (C₉₋₂₀₀₀ arylalkylanhydride)₁₋₁₀₀, (C₂₋₃₀ alkyl carbonate)₁₋₁₀₀, (C₇₋₅₀ arylcarbonate)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylaryl carbonate)₁₋₁₀₀, (C₈₋₂₀₀₀ arylalkylcarbonate)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀ alkylaryl ether, or C₇₋₂₀₀₀arylalkyl ether)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b) or Ar—R¹—Ar)—NH—CO—O—(C₂₋₅₀alkyl ester, C₇₋₆₀ aryl ester, C₈₋₂₀₀₀ alkylaryl ester, or C₈₋₂₀₀₀arylalkyl ester)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀alkylaryl ether, or C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—, —R^(a)—O—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀ aryl ester, C₈₋₂₀₀₀alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀—R^(c)—O—CO—NH—(R^(b)or Ar—R^(b)—Ar)—NH—CO—O—, —R^(a)—NH—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀alkylaryl ether, or C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀aryl ester, C₈₋₂₀₀₀ alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀aryl ether, C₇₋₂₀₀₀ alkylaryl ether, or C₇₋₂₀₀₀ arylalkylether)₁₋₁₀₀—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀aryl ester, C₈₋₂₀₀₀ alkylaryl ester, or C₈₋₂₀₀₀ arylalkylester)₁₋₁₀₀—R^(c)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—,—R^(a)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—NH—(C₂₋₅₀ alkyl amide, C₇₋₆₀aryl amide, C₈₋₂₀₀₀ alkylaryl amide, or C₈₋₂₀₀₀ arylalkyl amide)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—NH—(C₂₋₅₀ alkyl amide,C₇₋₆₀ aryl amide, C₈₋₂₀₀₀ alkylaryl amide, or C₈₋₂₀₀₀ arylalkylamide)₁₋₁₀₀, or a bond; each Z, independently, is —G—D, wherein G is—R^(a)—, —R^(a)—Ar—, —Ar—R^(a)—, or —Ar—; and D is —H, —OH, —SH, —NH₂,—NHOH, —SO₃H, —OSO₃H, —CO₂H, —CONH₂, —CONHNH₂, —CH(NH₂)—CO₂H,—NH—CH₂—CO₂H, —P(OH)₃, —PO(OH)₂, —O—PO(OH)₂, —O—PO(OH)—O—PO(OH)₂,—O—PO(O⁻)—O—CH₂CH₂NH₃ ⁺, —O—PO(O⁻)—O—CH₂CH₂—N⁺(CH₃)₃, -glycoside,-oligosaccharide, —CO-glycoside, —CO-oligosaccharide, —OCH₃,—OCH₂(CHOH)₄—CH₂OH, —OCH₂(CHOH)₂—CH₂OH, —CO—OCH₂(CHOH)₄—CH₂OH,—C₆H₃(OH)₂, —N(CH₂CO₂H)₂, —CO—N(CH₂CO₂H)₂, —CO—NH—C(CH₂CH₂CO₂H)₃,—CO—NH—C(CH₂CH₂OH)₃, —[CH₂—CH(CO₂R^(a))]₁₋₁₀₀—H, —NH₃ ⁺, —N⁺H₂R^(a),—N⁺HR^(a)R^(b), or —N⁺R^(a)R^(b)R^(c). Each of R^(a), R^(b), and R^(c),independently, is C₁₋₂₀ alkyl and Ar is aryl. q is 0-30, and m is 0-30.Note that the sum of q and m is 0-30. Each of R¹ and R⁴, independently,is ═O or C₁₋₂₀ hydrocarbon. A hydrocarbon is a moiety containing carbonand hydrogen, e.g., alkyl, alkenyl, or alkynyl. Each of R² and R⁵,independently, is C₁₋₂₀ hydrocarbon; wherein R¹ and R², or R⁴ and R⁵ canjoin together to form C₆₋₄₀ aryl which is optionally substituted withhalide, —OH, —NHNH₂, —NH₂OH, —NH—CH₂—CO₂H, —CH₂—CH₂—D, —CH₂—B—Z,—CO—CH₂—D, —CO—B—Z, —O—B—Z, or —NH—B—Z. Each of R³ and R⁶,independently, is —H, —CH₂—D, —B—Z, —G—E, —G—CO—E, or a side chain of anamino acid. E is E₁, E₂, or E₃, in which E₁ is Y₁,Y₂-amino,(Y₁,Y₂-alkyl)-amino, Y₁,Y₂-ethylenediamino, (dihydroxymethyl)alkylamino,(X₁,X₃-aryl)amino, or X₁,X₃-aryloxy; E₂ is Y₁,Y₂-alkoxy,(Y₁,Y₂-amino)alkoxy, (Y₁,Y₂,Y₃-aryl)oxy, (dihydroxyalkyl)-aryloxy,(Y₁,Y₂,Y₃-alkyl)amino, (Y₁,Y₂,Y₃-aryl)amino, dihydroxyalkylamino,Y₁,Y₂,Y₃-alkoxy, (trihydroxyalkyl)alkoxy, (trihydroxyalkyl)alkylamino,(dicarboxyalkyl)amino, (Y₁,Y₂,Y₃-alkyl)thio, (X₁,X₃-aryl)thio,(Y₁,Y₂-alkyl)thio, (dihydroxyalkyl)thio, Y₁,Y₂-dioxoalkyl, ortri-(Y₁,Y₂,Y₃-methylaminocarboxyethyl)methylamino; and E₃ is((glycoside)oxoheteroaryl)amino, ((glycosidyl)oxoaryl)amino,(X₁,X₂,X₃-heteroaryl)amino, (X₁-diarylketone)amino, (X,X₁-oxoaryl)amino,(X,X₁-dioxoaryl)amino, (Y₁-alkyl,Y₂-alkyldioxoheteroaryl)amino,(Y₁-alkyl,Y₂-alkyldioxoaryl)amino,(di(Y₁,Y₂-methyl)dioxoheteroaryl)amino,(di(Y₁,Y₂-methyl)dioxoaryl)amino, ((glycosidyl)heteroaryl)amino,((glycosidyl)aryl)amino, ((carboxylacetylalkyl)oxo-heteroaryl)amino,((carboxylacetylalkyl)oxoaryl)amino,((isopropylaminohydroxy-alkoxy)aryl)amino, (X₁,X₂,X₃-alkylaryl)amino,(X₁,X₂,X₃-heteroaryl)oxy, (isopropylaminohydroxyalkyl)aryloxy,(X₁,X₂,X₃-oxoheteroaryl)oxy, (X₁,X₂,X₃-oxoaryl)oxy,(X₁,Y₁-oxoheteroaryl)oxy, (X₁-diarylketone)oxy, (X,X₁-oxoaryl)oxy,(X₁,X₂-dioxoayl)oxy, (Y₁,Y₂,di-aminodihydroxy)alkyl,(X₁,X₂-heteroaryl)thio, ((tricarboxylalkyl)ethylene-diamino)alkoxy,(X₁,X₂-oxoaryl)thio, (X₁,X₂-dioxoaryl)thio, (glycosidylheteroaryl)thio,(glycosidylaryl)thio, Y₁-alkyl(thiocarbonyl)thio,Y₁,Y₂,-alkyl(thiocarbonyl)thio, Y₁,Y₂,Y₃-alkyl(thiocarbonyl)thio,(Y₁,Y₂-aminothiocarbonyl)thio, (pyranosyl)thio, cysteinyl, tyrosinyl,(phenylalainyl)amino, (dicarboxyalkyl)thio, (aminoaryl)₁₋₁₀₀amino,(pyranosyl)amino, (Y₁-aminoaryl)₁₋₁₀₀amino,(amino(sulfoaryl))₁₋₁₀₀amino, peptidyl, thymidinyl, uridinyl,guanosinyl, adenosinyl, cholesteryl, or biotinylalkoxy. X is halide.Each of X₁, X₂, and X₃, independently, is —Y₁, —O—Y₁, —S—Y₁, —NH—Y₁,—CO—O—Y₁, —O—CO—Y₁, —CO—NH—Y₁, —CO—NY₁Y₂, —NH—CO—Y₁, —SO₂—Y₁, —CHY₁Y₂,or —NY₁Y₂. Each of Y₁, Y₂, and Y₃, independently, is —Z or —B—Z. Each ofx and y, independently, is 0 or 1; and s is 1-6. Note that when x is 0,R¹ is ═O; that when y is 0, R⁴ is ═O; that when x is 1, R¹ and R² jointogether to form C₆₋₄₀ aryl; and that when y is 1, R⁴ and R⁵ jointogether to form C₆₋₄₀ aryl.

Another aspect of this invention relates to a method for preparing acompound of formula (I). The method includes reacting a compound offormula (II):

wherein M is a Cu, Mn, Fe, Co, Ni, Ru, Rh, Os, Zn, Cr, Ti, or Zr ion,with a fullerene compound F_(f) of the formula F(—K)_(m)(—Y—Z)_(q)wherein the sum of q and m is 0 to form a compound of formula (III):

M is then removed from a compound of formula (III), e.g., by using anion exchange resin such as Dowex, to form a compound of formula (I)wherein the sum of q and m is 0. The compound of formula (I) wherein thesum of q and m is 0 can be further treated with a nitrating or sulfatingagent to form a nitrofullerene or cyclosulfated fullerene, andcontacting the nitrofullerene or cyclosulfated fullerene with anucleophilic agent to form a compound of formula (I) wherein the sum ofq and m is greater than 0, i.e., a derivatized fulleropyrrolidinecompound of this invention.

The compound of formula (II) can be prepared by reacting a compound offormula (IV):

with a metal salt MX, wherein M is a Cu, Mn, Fe, Co, Ni, Ru, Rh, Os, Zn,Cr, Ti, or Zr ion, and X is an anion such as sulfate, halide, acetate,and nitrate. As to the compound of formula (IV), it is prepared byreacting a compound of formula (V):

with a compound of formula (VI):

Yet another aspect of this invention relates to a compound of formula(VII).

F_(f) is F(—K)_(m)(—Y—Z)_(q). F is a fullerene core. Each K,independently, is —OH, —SH, —NH₂, —NHOH, —SO₃H, —OSO₃H, —CO₂H, —CONH₂,—CONHNH₂, —P(OH)₃, —PO(OH)₂, —O—PO(OH)₂, —O—PO(OH)—O—PO(OH)₂,—O—PO(O⁻)—O—CH₂CH₂—NH₃ ⁺, —O—PO(O⁻)—O—CH₂CH₂—N⁺(CH₃)₃, -glycoside,—OCH₃, —OCH₂(CHOH)₄—CH₂OH, —OCH₂(CHOH)₂—CH₂OH, —NH—CH₂—CO₂H,—[CH(CO₂H)—CH₂]₁₋₁₀₀—OH, —[CH(CO₂R^(a))—CH₂]₁₋₁₀₀—OH,—[C(CH₃)(CO₂H)—CH₂]₁₋₁₀₀—OH, —[C(CH₃)(CO₂R^(a))—CH₂]₁₋₁₀₀—OH, —N(OH)₂,—NH₃ ⁺, —N⁺H₂R^(a), —N⁺R^(a)R^(b), or —N⁺R^(a)R^(b)R^(c). Each Y is—A—B—, in which A is —O—, —NH—, —S—, —CO—O—, —O—CO—, —O—CO—O—,—O—CO—NH—, —NH—CO—NH—, —CO—NH—, or —NH—CO—; and B is—R^(a)—O—[Si(CH₃)₂—O—]₁₋₁₀₀, C₁₋₂₀₀₀ alkyl, C₆₋₄₀ aryl, C₇₋₂₀₀₀alkylaryl, C₇₋₂₀₀₀ arylalkyl, (C₁₋₃₀ alkyl ether)₁₋₁₀₀, (C₆₋₄₀ arylether)₁₋₁₀₀, (C₇₋₂₀₀₀ alkylaryl ether)₁₋₁₀₀, (C₇₋₂₀₀₀ arylalkylether)₁₋₁₀₀, (C₁₋₃₀ alkyl thioether)₁₋₁₀₀, (C₆₋₄₀ aryl thioether)₁₋₁₀₀,(C₇₋₂₀₀₀ alkylaryl thioether)₁₋₁₀₀, (C₇₋₂₀₀₀ arylalkyl thioether)₁₋₁₀₀,(C₂₋₅₀ alkyl ester)₁₋₁₀₀, (C₇₋₂₀₀₀ aryl ester)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylarylester)₁₋₁₀₀, (C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀, —R^(a)—CO—O—(C₁₋₃₀ alkylether)₁₋₁₀₀, —R^(a)—CO—O—(C₆₋₄₀ aryl ether)₁₋₁₀₀, —R^(a)—CO—O—(C₇₋₂₀₀₀alkylaryl ether)₁₋₁₀₀, —R^(a)—CO—O—(C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀,(C₄₋₅₀ alkyl urethane)₁₋₁₀₀, (C₁₄₋₆₀ aryl urethane)₁₋₁₀₀, (C₁₀₋₂₀₀₀alkylaryl urethane)₁₋₁₀₀, (C₁₀₋₂₀₀₀ arylalkyl urethane)₁₋₁₀₀, (C₅₋₅₀alkyl urea)₁₋₁₀₀, (C₁₄₋₆₀ aryl urea)₁₋₁₀₀, (C₁₀₋₂₀₀₀ alkylarylurea)₁₋₁₀₀, (C₁₀₋₂₀₀₀ arylalkyl urea)₁₋₁₀₀, (C₂₋₅₀ alkyl amide)₁₋₁₀₀,(C₇₋₆₀ aryl amide)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylaryl amide)₁₋₁₀₀, (C₈₋₂₀₀₀arylalkyl amide)₁₋₁₀₀, (C₃₋₃₀ alkyl anhydride)₁₋₁₀₀, (C₈₋₅₀ arylanhydride)₁₋₁₀₀, (C₉₋₂₀₀₀ alkylaryl anhydride)₁₋₁₀₀, (C₉₋₂₀₀₀ arylalkylanhydride)₁₋₁₀₀, (C₂₋₃₀ alkyl carbonate)₁₋₁₀₀, (C₇₋₅₀ arylcarbonate)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylaryl carbonate)₁₋₁₀₀, (C₈₋₂₀₀₀ arylalkylcarbonate)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀ alkylaryl ether, or C₇₋₂₀₀₀arylalkyl ether)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀ aryl ester, C₈₋₂₀₀₀alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b)or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀alkylaryl ether, or C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—, —R^(a)—O—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀ aryl ester, C₈₋₂₀₀₀alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀—R^(c)—O—CO—NH—(R^(b)or Ar—R^(b)—Ar)—NH—CO—O—, —R^(a)—NH—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀alkylaryl ether, or C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀aryl ester, C₈₋₂₀₀₀ alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀aryl ether, C₇₋₂₀₀₀ alkylaryl ether, or C₇₋₂₀₀₀ arylalkylether)₁₋₁₀₀—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀aryl ester, C₈₋₂₀₀₀ alkylaryl ester, or C₈₋₂₀₀₀ arylalkylester)₁₋₁₀₀—R^(c)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—,—R^(a)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—NH—(C₂₋₅₀ alkyl amide, C₇₋₆₀aryl amide, C₈₋₂₀₀₀ alkylaryl amide, or C₈₋₂₀₀₀ arylalkyl amide)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—NH—(C₂₋₅₀ alkyl amide,C₇₋₆₀ aryl amide, C₈₋₂₀₀₀ alkylaryl amide, or C₈₋₂₀₀₀ arylalkylamide)₁₋₁₀₀, or a bond; each Z, independently, is —G—D, wherein G is—R^(a)—, —R^(a)—Ar—, —Ar—R^(a)—, or —Ar—; and D is —H, —OH, —SH, —NH₂,—NHOH, —SO₃H, —OSO₃H, —CO₂H, —CONH₂, —CONHNH₂, —CH(NH₂)—CO₂H,—NH—CH₂—CO₂H, —P(OH)₃, —PO(OH)₂, —O—PO(OH)₂, —O—PO(OH)—O—PO(OH)₂,—O—PO(O⁻)—O—CH₂CH₂NH₃ ⁺, —O—PO(O⁻)—O—CH₂CH₂—N⁺(CH₃)₃, -glycoside,-oligosaccharide, —CO-glycoside, —CO-oligosaccharide, —OCH₃,—OCH₂(CHOH)₄—CH₂OH, —OCH₂(CHOH)₂—CH₂OH, —CO—OCH₂(CHOH)₄—CH₂OH,—C₆H₃(OH)₂, —N(CH₂CO₂H)₂, —CO—N(CH₂CO₂H)₂, —CO—NH—C(CH₂CH₂CO₂H)₃,—CO—NH—C(CH₂CH₂OH)₃, —[CH₂—CH(CO₂R^(a))]₁₋₁₀₀—H, —NH₃ ⁺, —N⁺H₂R^(a),—N⁺HR^(a)R^(b) , or —N⁺R^(a)R^(b)R^(c). Each of R^(a), R^(b), and R^(c),independently, is C₁₋₂₀ alkyl and Ar is aryl. q is 0-30, and m is 0-30.Note that the sum of q and m is 0-30. Each of R¹ and R⁴, independently,is ═O or C₁₋₂₀ hydrocarbon. Each of R² and R⁵, independently, is C₁₋₂₀hydrocarbon. R¹ and R², or R⁴ and R⁵ can join together to form C₆₋₄₀aryl which is optionally substituted with halide, —OH, —NHNH₂, —NH₂OH,—NH—CH₂—CO₂H, —CH₂—CH₂—D, —CH₂—B—Z, —CO—CH₂—D, —CO—B—Z, —O—B—Z, or—NH—B—Z. Each of R³ and R⁶, independently, is —H, —CH₂—D, —B—Z, —G—E,—G—CO—E or a side chain of an amino acid. Each of B, D, and Z havingbeen defined above. E is E₁, E₂, or E₃, in which E₁ is Y₁,Y₂-amino,(Y₁,Y₂-alkyl)-amino, Y₁,Y₂-ethylenediamino,(dihydroxymethyl)-alkylamino, (X₁,X₃-aryl)amino, or X₁,X₃-aryloxy; E₂ isY₁,Y₂-alkoxy, (Y₁,Y₂-amino)alkoxy (Y₁,Y₂,Y₃-aryl)oxy,(dihydroxyalkyl)-aryloxy, (Y₁,Y₂,Y₃-alkyl)amino, (Y₁,Y₂,Y₃-aryl)amino,dihydroxyalkylamino, Y₁,Y₂,Y₃-alkoxy, (trihydroxyalkyl)alkoxy,(trihydroxyalkyl)-alkylamino, (dicarboxyalkyl)amino,(Y₁,Y₂,Y₃-alkyl)thio, (X₁,X₃-aryl)thio, (Y₁,Y₂-alkyl)thio,(dihydroxyalkyl)thio, Y₁,Y₂-dioxoalkyl, ortri-(Y₁,Y₂,Y₃-methylaminocarboxyethyl)methylamino; and E₃ is((glycosidyl)oxoheteroaryl)amino, ((glycosidyl)oxoaryl)amino,(X₁,X₂,X₃-heteroaryl)amino, (X₁-diarylketone)amino, (X,X₁-oxoaryl)amino,(X,X₁-dioxoaryl)amino, (Y₁-alkyl,Y₂-alkyldioxoheteroaryl)amino,(Y₁-alkyl,Y₂-alkyldioxoaryl)amino,(di(Y₁,Y₂-methyl)dioxoheteroaryl)amino,(di(Y₁,Y₂-methyl)dioxoaryl)amino, ((glycosidyl)heteroaryl)amino,((glycosidyl)aryl)amino, ((carboxylacetylalkyl)oxo-heteroaryl)amino,((carboxylacetylalkyl)oxoaryl)amino,((isopropylaminohydroxy-alkoxy)aryl)amino, (X₁,X₂,X₃-alkylaryl)amino,(X₁,X₂,X₃-heteroaryl)oxy, (isopropylaminohydroxyalkyl)aryloxy,(X₁,X₂,X₃-oxoheteroaryl)oxy, (X₁,X_(2,)X₃-oxoaryl)oxy,(X₁,Y₁-oxoheteroaryl)oxy, (X₁-diarylketone)oxy, (X,X₁-oxoaryl)oxy,(X₁,X₂-dioxoaryl)oxy, (Y₁,Y₂,di-aminodihydroxy)alkyl,(X₁,X₂-heteroaryl)thio, ((tricarboxylalkyl)ethylene-diamino)alkoxy,(X₁,X₂-oxoaryl)thio, (X₁,X₂-dioxoaryl)thio, (glycosidylheteroaryl)thio,(glycosidylaryl)thio, Y₁-alkyl(thiocarbonyl)thio,Y₁,Y₂,-alkyl(thiocarbonyl)thio, Y₁,Y₂,Y₃-alkyl(thiocarbonyl)thio,(Y₁,Y₂-aminothio-carbonyl)thio, (pyranosyl)thio, cysteinyl, tyrosinyl,(phenylalainyl)amino, (dicarboxyalkyl)thio, (aminoaryl)₁₋₁₀₀amino,pyranosyl)amino, (Y₁-aminoaryl)₁₋₁₀₀amino, (amino(sulfoaryl))₁₋₁₀₀amino,peptidyl, thymidinyl, uridinyl, guanosinyl, adenosinyl, cholesteryl, orbiotinylalkoxy. X is halide. Each of X₁, X₂, and X₃, independently, is—Y₁, —O—Y₁, —S—Y₁, —NH—Y₁, —CO—O—Y₁, —O—CO—Y₁, —CO—NH—Y₁, —CO—NY₁Y₂,—NH—CO—Y₁, —SO₂—Y₁, —CHY₁Y₂, or —NY₁Y₂. Each of Y₁, Y₂, and Y₃,independently, is —Z or —B—Z. R⁷ is —R^(d) or —O—R^(e). R^(d) is —OH,—OM, —NHNH₂, —NHOH, —NH—CH₂—CO₂H, —O—B—Z, —NH—B—Z, —E, —O—G—E, —NH—G—E,—O—G—CO—E, or —NH—G—CO—E. M is Cu, Mn, Fe, Co, Ni, Ru, Rh, Os, Zn, Cr,Ti, or Zr ion. R^(e) is —H, —CH₂—CH₂—D, —CH₂—B—Z, CH₂—G—E, —CH₂—G—CO—E,—CO—CH₂—D, —CO—B—Z, —CO—G—E, or —CO—G—CO—E. R⁸ is R^(e). R⁹ is —O—or abond. R¹⁰ is —R^(d) or —R^(e). Each of x and y, independently, is 0 or1; and p is 1-30. Note that when x is 0, R¹ is ═O, and R⁷ is —R^(d);that when y is 0, R₄ is ═O, and R⁹ is a bond, and R¹⁰ is —R^(d); thatwhen x is 1, R¹ and R² join together to form C₆₋₄₀ aryl, and R⁷ is—O—R^(e); and that when y is 1, R⁴ and R⁵ join together to form C₆₋₄₀aryl, R⁹ is —O—, and R¹⁰ is —R^(e). In addition, when p is greater than1, x is 0.

Still another aspect of this invention relates to a compound of formula(VIII):

F_(f) is F(—K)_(m)(—Y—Z)_(q). F is a fullerene core. Each K,independently, is —OH, —SH, —NH₂, —NHOH, —SO₃H, —OSO₃H, —CO₂H, —CONH₂,—CONHNH₂, —P(OH)₃, —PO(OH)₂, —O—PO(OH)₂, —O—PO(OH)—O—PO(OH)₂,—O—PO(O⁻)—O—CH₂CH₂—NH₃ ⁺, —O—PO(O⁻)—O—CH₂CH₂—N⁺(CH₃)₃, -glycoside,—OCH₃, —OCH₂(CHOH)₄—CH₂OH, —OCH₂(CHOH)₂—CH₂OH, —NH—CH₂—CO₂H,—[CH(CO₂H)—CH₂]₁₋₁₀₀—OH, —[CH(CO₂R^(a))—CH₂]₁₋₁₀₀—OH,—[C(CH₃)(CO₂H)—CH₂]₁₋₁₀₀—OH, —[C(CH₃)(CO₂R^(a))—CH₂]₁₋₁₀₀—OH, —N(OH)₂,—NH₃ ⁺, —N⁺H₂R^(a), —N⁺HR^(a)R^(b), or —N⁺R^(a)R^(b)R^(c); each Y is—A—B—, in which A is —O—, —NH—, —S—, —CO—O—, —O—CO—, —O—CO—O—, —CO—NH—,—NH—CO—NH—, —CO—NH—, or —NH—CO—. B is —R^(a)—O—[Si(CH₃)₂—O—]₁₋₁₀₀,C₁₋₂₀₀₀ alkyl, C₆₋₄₀ aryl, C₇₋₂₀₀₀ alkylaryl, C₇₋₂₀₀₀ arylalkyl, (C₁₋₃₀alkyl ether)₁₋₁₀₀, (C₆₋₄₀ aryl ether)₁₋₁₀₀, (C₇₋₂₀₀₀ alkylarylether)₁₋₁₀₀, (C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀, (C₁₋₃₀ alkylthioether)₁₋₁₀₀, (C₆₋₄₀ aryl thioether)₁₋₁₀₀, (C₇₋₂₀₀₀ alkylarylthioether)₁₋₁₀₀, (C₇₋₂₀₀₀ arylalkyl thioether)₁₋₁₀₀, (C₂₋₅₀ alkylester)₁₋₁₀₀, (C₇₋₂₀₀₀ aryl ester)₁₋₁₀₀, (C₈₋₂₀₀₀ alkyaryl ester)₁₋₁₀₀,(C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀, —R^(a)—CO—O—(C₁₋₃₀ alkyl ether)₁₋₁₀₀,—R^(a)—CO—O—(C₆₋₄₀ aryl ether)₁₋₁₀₀, —R^(a)—CO—O—(C₇₋₂₀₀₀ alkylarylether)₁₋₁₀₀, —R^(a)—CO—O—(C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀, (C₄₋₅₀ alkylurethane)₁₋₁₀₀, (C₁₄₋₆₀ aryl urethane)₁₋₁₀₀, (C₁₀₋₂₀₀₀ alkylarylurethane)₁₋₁₀₀, (C₁₀₋₂₀₀₀ arylalkyl urethane)₁₋₁₀₀, (C₅₋₅₀ alkylurea)₁₋₁₀₀, (C₁₄₋₆₀ aryl urea)₁₋₁₀₀, (C₁₀₋₂₀₀₀ alkylaryl urea)₁₋₁₀₀,(C₁₀₋₂₀₀₀ arylalkyl urea)₁₋₁₀₀, (C₂₋₅₀ alkyl amide)₁₋₁₀₀, (C₇₋₆₀arylamide)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylaryl amide)₁₋₁₀₀, (C₈₋₂₀₀₀ arylalkylamide)₁₋₁₀₀, (C₃₋₃₀ alkyl anhydride)₁₋₁₀₀, (C₈₋₅₀ arylanhydride)_(1-100, (C) ₉₋₂₀₀₀ alkylaryl anhydride)₁₋₁₀₀, (C₉₋₂₀₀₀arylalkyl anhydride)₁₋₁₀₀, (C₂₋₃₀ alkyl carbonate)₁₋₁₀₀, (C₇₋₅₀ arylcarbonate)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylary carbonate)₁₋₁₀₀, (C₈₋₂₀₀₀ arylalkylcarbonate)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀ alkylaryl ether, or C₇₋₂₀₀₀arylalkyl ether)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀ aryl ester, C₈₋₂₀₀₀alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b)or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀alkylaryl ether, or C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—, —R^(a)—O—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀ aryl ester, C₈₋₂₀₀₀alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀—R^(c)—O—CO—NH—(R^(b)or Ar—R^(b)—Ar)—NH—CO—O—, —R^(a)—NH—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀alkylaryl ether, or C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀aryl ester, C₈₋₂₀₀₀ alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀aryl ether, C₇₋₂₀₀₀ alkylaryl ether, or C₇₋₂₀₀₀ arylalkylether)₁₋₁₀₀—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀aryl ester, C₈₋₂₀₀₀ alkylaryl ester, or C₈₋₂₀₀₀ arylalkylester)₁₋₁₀₀—R^(c)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—,—R^(a)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—NH—(C₂₋₅₀ alkyl amide, C₇₋₆₀aryl amide, C₈₋₂₀₀₀ alkylaryl amide, or C₈₋₂₀₀₀ arylalkyl amide)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—NH—(C₂₋₅₀ alkyl amide,C₇₋₆₀ aryl amide, C₈₋₂₀₀₀ alkylaryl amide, or C₈₋₂₀₀₀ arylalkylamide)₁₋₁₀₀, or a bond. Each Z, independently, is —G—D, wherein G is—R^(a)—, —R^(a)—Ar—, —Ar—R^(a)—, or —Ar—; and D is —H, —OH, —SH, —NH₂,—NHOH, —SO₃H, —OSO₃H, —CO₂H, —CONH₂, —CONHNH₂, —CH(NH₂)—CO₂H,—NH—CH₂—CO₂H, —P(OH)₃, —PO(OH)₂, —O—PO(OH)₂, —O—PO(OH)—O—PO(OH)₂,—O—PO(O⁻)—O—CH₂CH₂NH₃ ⁺, —O—PO(O⁻)—O—CH₂CH₂—N⁺(CH₃)₃, -glycoside,-oligosacchamide, —CO-glycoside, —CO-oligosacchamide, —OCH₃,—OCH₂(CHOH)₄—CH₂OH, —OCH₂(CHOH)₂—CH₂OH, —CO—OCH₂(CHOH)₄—CH₂OH,—C₆H₃(OH)₂, —N(CH₂CO₂H)₂, —CO—N(CH₂CO₂H)₂, —CO—NH—C(CH₂CH₂CO₂H)₃,—CO—NH—C(CH₂CH₂OH)₃, —[CH₂——CH(CO₂R^(a))]₁₋₁₀₀—H, —NH₃ ⁺, —N⁺H₂R^(a),—N⁺HR^(a)R^(b), or —N⁺R^(a)R^(b)R^(c). Each of R^(a), R^(b), and R^(c),independently, is C₁₋₂₀ alkyl and Ar is aryl. q is 0-30, and m is 0-30.Note that the sum of q and m is 0-30. Each of R¹ and R⁴, independently,is ═O or C₁₋₂₀ hydrocarbon; and each of R² and R⁵, independently, isC₁₋₂₀ hydrocarbon. R¹ and R², or R⁴ and R⁵ can join together to formC₆₋₄₀ aryl which is optionally substituted with halide, —OH, —NHNH₂,—NH₂OH, —NH—CH₂—CO₂H, —CH₂—CH₂—D, —CH₂—B—Z, —CO—CH₂—D, —CO—B—Z, —O—B—Z,or —NH—B—Z. Each of R³ and R⁶, independently, is —H, —CH₂—D, —B—Z, —G—E,—G—CO—E or a side chain of an amino acid. E is E₁, E₂, or E₃, in whichE₁ is Y₁,Y₂-amino, (Y₁,Y₂-alkyl)-amino, Y₁,Y₂-ethylenediamino,(dihydroxymethyl)alkylamino, (X₁,X₃-aryl)amino, or X₁,X₃-aryloxy; E₂ isY₁,Y₂-alkoxy, (Y₁,Y2-amino)alkoxy, (Y₁,Y₂,Y₃-aryl)oxy,(dihydroxyalkyl)-aryloxy, (Y₁,Y₂,Y₃-alkyl)amino, (Y₁,Y₂,Y₃-aryl)amino,dihydroxyalkylamino, Y₁,Y₂,Y₃-alkoxy, (trihydroxyalkyl)alkoxy,(trihydroxyalkyl)alkylamino, (dicarboxyalkyl)amino,(Y₁,Y₂,Y₃-alkyl)thio, (X₁,X₃-aryl)thio, (Y₁,Y₂-alkyl)thio,(dihydroxyalkyl)thio, Y₁,Y₂-dioxoalkyl, ortri-(Y₁,Y₂,Y₃-methylaminocarboxyethyl)methylamino; and E₃ is((glycosidyl)oxoheteroaryl)amino, ((glycosidyl)oxoaryl)amino,(X₁,X₂,X₃-heteroaryl)amino, (X₁-diarylketone)amino, (X,X₁-oxoaryl)amino,(X,X₁-dioxoaryl)amino, (Y₁-alkyl,Y₂-alkyldioxoheteroaryl)amino,(Y₁-alkyl,Y₂-alkyldioxoaryl)amino,(di(Y₁,Y₂-methyl)dioxoheteroaryl)amino,(di(Y₁,Y₂-methyl)dioxoaryl)amino, ((glycosidyl)heteroaryl)aamino,((glycosidyl)aryl)amino, ((carboxylacetylalkyl)oxo-heteroaryl)amino,((carboxylacetylalkyl)oxoaryl)amino,((isopropylaminohydroxy-alkoxy)aryl)amino, (X₁,X₂,X₃-alkylaryl)amino,(X₁,X₂,X₃-heteroaryl)oxy, (isopropylaminohydroxyalkyl)aryloxy,(X₁,X₂,X₃-oxoheteroaryl)oxy, (X₁,X₂,X₃-oxoaryl)oxy,(X₁,Y₁-oxoheteroaryl)oxy, (X₁-diarylketone)oxy, (X,X₁-oxoaryl)oxy,(X₁,X₂-dioxoaryl)oxy, (Y₁,Y₂,di-aminodihydroxy)alkyl,(X₁,X₂-heteroaryl)thio, ((tricarboxylalkyl)ethylene-diamino)alkoxy,(X₁,X₂-oxoaryl)thio, (X₁,X₂-dioxoaryl)thio, (glycosidylheteroaryl)thio,(glycosidylaryl)thio, Y₁-alkyl(thiocarbonyl)thio, Y₁,Y₂,-alkyl(thiocarbonyl)thio, Y₁,Y₂,Y₃-alkyl(thiocarbonyl)thio,(Y₁,Y₂-aminothiocarbonyl)thio, (pyranosyl)thio, cysteinyl, tyrosinyl,(phenylalainyl)amino, (dicarboxyalkyl)thio, (aminoaryl)₁₋₁₀₀amino,(pyranosyl)amino, (Y₁-amninoaryl)₁₋₁₀₀amino,(amino(sulfoaryl))₁₋₁₀₀amino, peptidyl, thymidinyl, uridinyl,guanosinyl, adenosinyl, cholesteryl, or biotinylalkoxy. X is halide.Each of X₁, X₂, and X₃, independently, is —Y₁, —O—Y₁, —S—Y₁, —NH—Y₁,—CO—O—Y₁, —O—CO—Y₁, —CO—NH—Y₁, —CO—NY₁Y₂, —NH—CO—Y₁, —SO₂—Y₁, —CHY₁Y₂,or —NY₁Y₂. Each of Y₁, Y₂, and Y₃, independently, is —Z or —B—Z. R⁷ is—R^(d) or —O—R^(d) is —OH, —OM, —NHNH₂, —NHOH, —NH—CH₂—CO₂H, —O—B—Z,—NH—B—Z, —E, —O—G—E, —NH—G—E, —O—G—CO—E, or —NH—G—CO—E. M is Cu, Mn, Fe,Co, Ni, Ru, Rh, Os, Zn, Cr, Ti, or Zr ion. R^(e) is —H, —CH₂—CH₂—D,—CH₂—B—Z, —CH₂—G—E, —CH₂—G—CO—E, —CO—CH₂—D, —CO—B—Z, —CO—G—E, or—CO—G—CO—E. R⁸ is R^(e) . R⁹ is —O—R^(f)— or —R^(g)—. R^(f) is—CO—B—G—O—, —CO—B—G—NH—, —CO—B—G—CO—O—, or —CO—B—G—CO—NH—. R^(g) is—NH—, —O—, —O—B—G—O—, —NH—B—G—O—, —NH—B—G—NH—, —O—CO—B—G—CO—O—, or—NH—CO—B—G—CO—NH—. R¹⁰ is —H. Each of x and y, independently, is 0 or 1;and r is 1-100. Note that when x is 0, R¹ is ═O, and R⁷ is —R^(d); thatwhen y is 0, R⁴ is ═O, and R⁹ is —R^(g), and R¹⁰ is —H; that when x is1, R¹ and R² join together to form C₆₋₄₀ aryl, and R⁷ is —O—R^(e); andthat when y is 1, R⁴ and R⁵ join together to form C₆₋₄₀ aryl, R⁹ is—O—R^(f), and R¹⁰ is —H. Further, when r is greater than 1, x is 0.

A salt of a compound of the present invention is also within the scopeof this invention. For example, a salt can form between an amino moietyand an anion such as sulfate, pyrosulfate bisulfate, sulfite, bisulfite,phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caprate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, or maleate.

As used herein, a fullerene core is C₆₀, C₆₁, C₆₂, C₆₃, C₆₄, C₆₅, C₇₀,C₇₆, C₇₈, C₈₂, C₈₄, or C₉₂, or La@C_(n), Ho@C_(n), Gd@C_(n), orEr@C_(n), in which n is 60, 74, or 82.

An amino acid is a molecule containing both an amino group and acarboxylic acid, e.g., alanine, aspartic acid, cysteine, glutamic acid,phenylalanine, halophenylalanine, hydroxyphenylalanine, glycine,histidine, isoleucine, lysine, leucine, methionine, asparagine,glytamine, arginine, serine, theronine, valine, tryptophan, tyrosine,2-aminobutyric acid, halophenylalanine, cyclohexylalanine, citrulline,homocitrulline, homoserine, norleucine, norvaline, or ornithine. Sidechain of an amino acid is the substituent that is bonded to the carbonatom adjacent to the carbonyl carbon, i.e., the -carbon atom. Forexample, the side chain of each of alanine and ornithine is —CH₃ andCH₂)₃NH₂, respectively. A peptidyl is a peptide moiety containing 2-100amino acid residues.

By the term “alkyl” is meant a straight chain that contains 1-30 carbonatoms, or a branched hydrocarbon chain of 3-30 carbon atoms, or cyclichydrocarbon groups containing 3-30 carbon atoms, or otherwise indicated.These alkyl groups may also contain one or more double bond or triplebond and the cyclic alkyl groups may contain one or more heteroatoms,which are, typically, nitrogen, oxygen, or sulfur. Examples of alkylgroups include, but are not limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, amyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl, pentadecyl, icosyl, allyl, 2-butenyl, 2-pentenyl,3-hexenyl, 4-decenyl, 5-nonadecenyl, 2-butnyl, 3-octnyl, 5-octadecnyl,cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbomyl,isobomyl, cyclopentyl-methyl, cyclohexylmethyl, 1- or 2-cyclohexylethyl,cyclo-pentenyl, cyclohexenyl, cycloheptenyl, cyclo-octenyl,tetra-hydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino andpyrrolindinyl groups.

As used herein, the term “aryl” refers to C₆₋₄₀ aromatic rings. Thesemoieties may also be fused rings and can be fused with aryl orheteroaryl which is as defined below. Fused rings are rings that share acommon carbon-carbon bond. Typically aryl groups include phenyl,naphthyl, biphenyl, indazolyl, phenanthryl, and anthracyl.

By the term “heteroaryl” in this disclosure is meant C₆₋₄₀ aromaticrings that contain one or more heteroatoms as defined above. Thesemoieties may also be fused rings. Examples of heteroaryl groups includepyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl,oxazolyl, imidazolyl, coumarinyl, indolyl, benzofuranyl, benzoxazolyl,benzothienyl, and benzothiadiazolyl.

As used herein, the term “halide” is defined as fluoro, chloro, bromo,or iodo. The term “nucleophilic agent” is defined as an electron-richspecies that donates electrons in a reaction. Examples of nucleophilicagents that can be employed in the preparation of derivatizedfulleropyrrolidines include amine, phenol, alkoxide, organothiolate,carbanion, organoamide anion, thiol, amino acid, and thiol carbamateanion. Note that the just-mentioned nucleophilic agents can beunsubstituted or substituted with other functional groups. Examples ofsubstituted nucleophilic agents include 1,4-naphthoquinonyl-amine,tyrosine, dihydroxypropylthiol, and the like.

The structures of many of the moieties mentioned above are shown belowwithin the pair of parentheses following each of the moieties: alkylether (—R—O—), aryl ether (—Ar—O—), alkylaryl ether (—R—Ar—O—),arylalkyl ether (—Ar—R—O—), alkyl thioether (—R—S—), aryl thioether(—Ar—S—), alkylaryl thioether (—R—Ar—S—), arylalkyl thioether(—Ar—R—S—), alkyl ester (—R—O—CO—, —R—CO—O—, —R₁—CO—O—R₂—O—CO—, or—R₁—O—CO—R₂—CO—O—), aryl ester (—Ar—O—CO—, —Ar—CO—O,—Ar₁—CO—O—Ar₂—O—CO—, or —Ar₁—O—CO—Ar₂—CO—O—), alkylaryl ester(—R—Ar—O—CO— or —R—Ar—CO—O—), arylalkyl ester (—Ar—R—O—CO— or—Ar—R—CO—O—), alkyl urethane (—R₁—O—CO—NH—R₂—NH—CO—O—), aryl urethane(—Ar₁—O—CO—NH—Ar₂—NH—CO—O—), alkylaryl urethane(—R₁—Ar—O—CO—NH—R₂—NH—CO—O—, —R—Ar₁—O—CO—NH—Ar₂—NH—CO—O—, or—R₁—O—CO—NH—Ar—R₂—Ar—NH—CO—O—), arylalkyl urethane(—Ar—R₁—O—CO—NH—R₂—NH—CO—O—, —Ar₁—R—O—CO—NH—Ar₂—NH—CO—O—, or—Ar₁—O—CO—NH—Ar₂—R—Ar₂—NH—CO—O—), alkyl urea(—R₁—NH—CO—NH—R₂—NH—CO—NH—), aryl urea (—Ar₁—NH—CO—NH—Ar₂—NH—CO—NH—),alkylaryl urea (—R₁—Ar—NH—CO—NH—R₂—NH—CO—NH—,—R—Ar₁—NH—CO—NH—Ar₂—NH—CO—NH—, or —R₁—NH—CO—NH—Ar—R₂—Ar—NH—CO—NH—),arylalkyl urea (—Ar—R₁—NH—CO—NH—R₂—NH—CO—NH—,—Ar₁—R—NH—CO—NH—Ar₂—NH—CO—NH—, or —Ar₁—NH—CO—NH—Ar₂—R—Ar₂—NH—CO—NH—),alkyl amide (—R—NH—CO—, —R—CO—NH—, —R₁—CO—NH—R₂—NH—CO—, or—R₁—NH—CO—R₂—CO—NH—), aryl amide (—Ar—NH—CO—, —Ar—CO—NH—,—Ar₁—CO—NH—Ar₂—NH—CO—, or —Ar₁—NH—CO—Ar₂—CO—NH—), alkylaryl amide(—R—Ar—NH—CO—, —R—CO—NH—Ar—NH—CO—, or —R—NH—CO—Ar—CO—NH—), arylalkylamide (—Ar—R—NH—CO—, —Ar—CO—NH—R—NH—CO—, or —Ar—NH—CO—R—CO—NH—), alkylanhydride (—R—CO—O—CO—), aryl anhydride (—Ar—CO—O—CO—), alkylarylanhydride (—R—Ar—CO—O—CO— or —R—CO—O—CO—Ar—CO—O—CO—), arylalkylanhydride (—Ar—R—CO—O—CO— or —Ar—CO—O—CO—R—CO—O—CO—), alkyl carbonate(—R—O—CO—O—), aryl carbonate (—Ar—O—CO—O—), alkylaryl carbonate(—R—Ar—O—CO—O— or —R—O—CO—O—Ar—O—CO—O—), and arylalkyl carbonate(—Ar—R—O—CO—O— or —Ar—O—CO—O—R—O—CO—O—). Note that the di-substitutionpattern on Ar can be para, meta, or ortho.

As will be discussed below, one can employ stereospecific compounds ofthis invention to treat patients suffering from cancer via photodynamictherapy. The stereospecific nature of these compounds allow specificinteractions with many biologically active compounds, e.g., proteinreceptors. The compounds of this invention can also be used to developchromatographic materials for purifying chiral molecules.

Other features and advantages of the present invention will be apparentfrom the following description of the preferred embodiments, and alsofrom the appending claims.

DETAILED DESCRIPTION

The invention relates to sterospecific fullerene compounds, i.e.,E-isomeric fulleropyrrolidine compounds, as well as polymers made ofsuch E-isomeric compounds. Also disclosed are methods for preparingthese E-isomeric compounds and E-isomeric fulleropyrrolidine polymers.

Methods of this invention allow an E-isomeric fulleropyrrolidinecompound to be prepared directly, thereby obviating the need topurifying a racemic mixture of both E- and Z-isomers. Separation ofoptical isomers is generally very difficult due to the close physicalproperties of optical isomers. Specifically, the methods describedherein utilize a key starting material, i.e., a bicyclicimine-containing organometallic compound such asN-pyruvylidenealaninatoaquocopper (II). This bicyclic imine-containingcompound, which is formed of two difunctional compounds, effects astereospecific cycloaddition reaction when reacts with a fullerene core,e.g., C₆₀, C₇₆, or Gd@C₈₂, thus forming only one fullerene isomer, i.e.,the E-isomer.

Scheme I below illustrates a method for preparing an E-isomericfulleropyrrolidine compound of this invention wherein its two carboxylicacid moieties are substituted at the same side of the pyrrolidinemoiety. In the first step, an amino acid (H₂N—CH(R_(b))—COOH) and apyruvic acid derivative (R_(b)—C(═O)—COOH) are used as exemplarydifunctional compounds which react with each other to form a bicyclicimine-containing copper (II) complex in the presence of copper (II)acetate. See step (i). Note that the coordination of the two carboxylicacid moieties with the copper (II) ion restricts rotations of the N—Cbond with respect to the N═C bond, thus forcing the two carboxylic acidto be at the same side of the pyrrolidine that is formed between theimine moiety, i.e., —C═N—C—, of the copper complex and a double bond ofa fullerene core, e.g., C₆₀, via a cycloaddition reaction. See step(ii). Not only does the copper (II) ion enables only one stereospecificisomer, i.e., the E-isomer, to be formed, it also prevents thermaldecarboxylation after dicarboxylic acid substituted fulleropyrrolidinesare formed. By exchanging the copper (II) ion with the proton on a Dowexresin (H⁺ form), the corresponding E-isomeric dicarboxylic acidsubstituted fulleropyrrolidine product was isolated in a high yield(>85%). See Example 1 below.

Scheme II below illustrates a method for preparing an E-isomericfulleropyrrolidine compound of this invention wherein it is substitutedwith a carboxylic acid and an aromatic ring at the same side of thepyrrolidine moiety. The only difference between the methods shown inScheme I and Scheme II lies in that the former method employs adifunctional carboxylic acid, e.g., 2-ketoglutaric acid, whereas thelatter method employs a difunctional phenol, e.g., salicylaldehyde. Thedifunctional phenol, e.g., a carbonyl-containing phenol, can then reactwith a difunctional carboxylic acid, e.g., an amino acid, in thepresence of a metal salt, e.g., Cu(OAc)₂ or CoCl₂, to form a bicyclicinline-containing metal complex. See step (i). The next two steps of themethod, i.e., cycloaddition (step (ii)) and removal of metal ions (step(iii)), are identical to those described above. See Example 7 below.

Alternatively, the bicyclic imine-containing organometallic compound canalso be formed between an amine-containing phenol, e.g.,2′-aminoacetophenone, and a carbonyl-containing carboxylic acid, e.g.,pyruvic acid, or a carbonyl-containing phenol, e.g., salicylaldehyde.

The resulting E-isomeric fulleropyrrolidine compound of formula (I) canbe further derivatized, e.g., by attaching thereto a methylglucoside, byvarious known methods. See, e.g., U.S. Pat. No. 6,020,523. For example,the fulleropyrrolidine compound can be treated with a nitrating agent ora sulfating agent to form a nitrofulleropyrrolidine or a cyclosulfatedfulleropyrrolidine intermediate, which can then be converted into aderivatized E-isomeric fulleropyrrolidine by reacting with anucleophilic agent. Examples of a nitrating agent include sodium nitriteand concentrated HNO₃, dinitrogen tetraoxide, nitrogen dioxide, andfuming nitric acid. Cyclosulfated fullerene intermediates, on the otherhand, can be formed by treating the fullerene with neat fuming sulfuricacid in the presence of an oxidant (e.g., P₂O₅, V₂O₅, or SeO₂). Examplesof a nucleophilic agent include primary and secondary organoaminocompound, alkoxide, organothiolate, organophenol compound, carbanion,organoamide anion, thiocarbamate ion, and the like.

The E-isomeric fulleropyrrolidine compound of formula (I) can furtherreact with each other to form a polymer (or an oligomer). The polymerformed can be a homopolymer or a copolymer, e.g., a random, a block, ora branched copolymer. Since a compound of formula (I) contains threetermini, i.e., a pyrrolidine nitrogen ring atom and two carboxylic acidmoieties (or a carboxylic moiety and a phenol hydroxy group, or twophenol hydroxyl groups), a number of polymers can be prepared viadifferent linkages. Take a fulleropyrrolidine compound containing twocarboxylic acid moieties as an example, a polymer can be formed bylinking the N-terminus (i.e., the pyrrolidine nitrogen ring atom) of afirst compound of formula (I) to the C-terminus (i.e., one of the twocarboxylic acid moieties) of a second compound of formula (I), and theN-terminus of this second compound of formula (I) can in turn be linkedto the C-terminus of a third compound of formula (I), and so on. Thispolymer design is similar to that of a peptide. The just-describedpolymer, i.e., a polymer of formula (VII), supra, can be prepared byforming an internal anhydride between the two carboxylic acid moieties,which is then treated with a base such as1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) to effect the polymerizationreaction. Due to the highly reactive nature of the anhydride moiety,derivatization of the fullerene should be done after the polymerizationstep. See Scheme III and Example 11 below.

A polymer of formula (VII) can also be prepared using afulleropyrrolidine compound having a phenol and a carboxylic acidmoiety. Since this compound (or monomer) contains one carboxylic acidand one amino group, polymerization can be effected by using commonpeptide coupling reagents, e.g., dicyclohexylcarbodiimide (DCC),benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate(BOP), or O-benzo-triazol-1-yl-N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU). Note that the hydroxy group of the phenolmoiety may need to be protected, e.g., by silyl ethers, duringpolymerization.

Alternatively, a polymer of an E-isomeric fulleropyrrolidine compound offormula (I) can also be formed by linking the carboxylic acid moiety (orthe hydroxy group of the phenol moiety) of one fulleropyrrolidinemonomer to the carboxylic acid moiety of another fulleropyrrolidinemonomer via a divalent linker, thus resulting in a polymer of formula(VII). For example, a polyamide and a polyester can be formed byreacting a fulleropyrrolidine compound with two carboxylic acid moietieswith a diamine (e.g., ethylenediamine) and a diol (e.g.,1,3-propanediol), respectively.

An E-isomeric fulleropyrrolidine compound of formula (I) can be used inphotodynamic therapy (PDT) to treat patients suffering from cancer. SeeExample 16 below. The photo-induced cytotoxicity of a fullerene compoundis connected with its ability to cleave DNA. Specifically,photogenerated triplet fullerene intermediate is involved in the energytransfer process which converts the ground-state triplet oxygenmolecules into the excited molecular singlet oxygen ¹O₂. Singlet oxygenis capable of inducing DNA damage and degeneration of other tissues thatlead to mutagenic effects on biological cells. The stereospecific natureof an E-isomeric fulleropyrrolidine compound of formula (I) can enhanceits affinity to DNA which is in the form of a double helix. Polymers offormulas (VII) and (VIII), which contain a plurality offulleropyrrolidine compounds of formula (I), can further enhance itsbiological activities by allowing delivery of multiplefulleropyrrolidine compounds in a single molecule.

A pharmaceutical composition containing an effective amount of afulleropyrrolidine compound of formula (I) (or a polymer formedtherefrom) is also within the scope of this invention. The use of such afulleropyrrolidine compound for the manufacture of a medicament fortreating tumors is also within the scope of this invention. Stillanother aspect of this invention is a method for treating tumor byadministering to a patient a pharmaceutical composition containing aneffective amount of a fulleropyrrolidine compound of this invention. Aneffective amount is defined as the amount which is required to confer atherapeutic effect on the treated patient, and is typically determinedbased on age, surface area, weight, and condition of the patient. Theinterrelationship of dosages for animals and humans (based on milligramsper meter squared of body surface) is described by Freireich et al.,Cancer Chemother. Rep. 1966, 50, 219. Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537.An effective amount of a pyridyl cyanoguanidine compound of thisinvention can range from about 1 mg/kg to about 150 mg/kg (e.g., about 1mg/kg to about 100 mg/kg). Effective doses will also vary, as recognizedby those skilled in the art, dependant on route of administration,excipient usage, and the possibility of co-usage with other therapeutictreatments including use of other antitumor agents and radiationtherapy.

The pharmaceutical composition may be administered via the parenteralroute, including orally, topically, subcutaneously, intraperitoneally,intramuscularly, and intravenously. Examples of parenteral dosage formsinclude aqueous solutions of the active agent, in a isotonic saline, 5%glucose or other well-known pharmaceutically acceptable excipient.Solubilizing agents such as cyclodextrin, or other solubilizing agentswell-known to those familiar with the art, can be utilized aspharmaceutical excipients for delivery of the therapeutic compounds.

A fulleropyrrolidine compound of this invention can be formulated intodosage forms for other routes of administration utilizing conventionalmethods. For, example, it can be formulated in a capsule, a gel seal, ora tablet for oral administration. Capsules may contain any standardpharmaceutically acceptable materials such as gelatin or cellulose.Tablets may be formulated in accordance with conventional procedures bycompressing mixtures of a pyridyl cyanoguanidine compound with a solidcarrier and a lubricant. Examples of solid carriers include starch andsugar bentonite. The fulleropyrrolidine compound can also beadministered in a form of a hard shell tablet or a capsule containing abinder, e.g., lactose or mannitol, a conventional filler, and atableting agent.

Without further elaboration, it is believed that one skilled in the artcan, based on the description herein, utilize the present invention toits fullest extent. The following specific examples are, therefore, tobe construed as merely illustrative, and not limitative of the remainderof the disclosure in any way whatsoever. All publications recitedherein, including patents, are hereby incorporated by reference in theirentirety.

EXAMPLE 1 Synthesis of E-isomer of1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylic Acid

In a conical flask charged with DL-alanine (2.25 g, 25 mmol) and amixture of water and ethanol (20 ml, 2:1) and stirred for a period of 20min was added pyruvic acid (2.2 g, 25 mmol). The reaction mixture wasstirred at ambient temperature for 1.0 h. The resulting yellowishsolution was then added copper (II) acetate (4.99 g, 25 mmol) inwater-ethanol (20 ml) and stirred for an additional 24 h, causingprecipitation of pale blue solids. The solids were filtered, washed withethanol, and dried to yield N-pyruvylidenealaninatoaquocopper (II)complex.

To a solution of C₆₀ (350 mg, 0.49 mmol) in o-dichlorobenzene (140 ml),N-pyruvylidenealaninatoaquocopper (II) complex (0.34 g, 1.96 mmol, 4.0equiv.) in pyridine (25 ml) was added via syringe under N₂. The solutionmixture was stirred for a period of 15 h at ambient temperature. It wasadded hexane (100 ml) to effect precipitation of solid products. Thesolid precipitates were isolated by centrifuge, washed with hexane (50ml), and dried in vaccuo. It was further washed twice by water, brine,and CH₃CN (20 ml each) and dried in vaccuo to afford brown solids of1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylatoaquocopper (II) complex(0.53 g). IR_(max) (KBr) 3424 (br, s), 1749 (w), 1716 (w), 1622 (s),1385 (s), 1218 (w), 1182 (w), 1154 (w), 1070 (w), 751, 696, and 525.

Brown solids of1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylatoaquocopper (II) complex(0.5 g) were dissolved in a mixture of pyridine (25 ml) and water (25ml). It was stirred in the presence of Dowex acid resin (50WX8, 2.0 g)for a period of 2.0 h. The solid resin was filtered off. The remainingsolution was stirred further with fresh Dowex acid resin (50WX8, 1.5 g)for an additional 30 min. At the end of the ion exchanging reaction,Dowex resin was filtered. After solvent evaporation of the filtrate, theresulting dark solids were washed with ethanol and dried in vaccuo togive the product of 1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylicacid (0.4 g). IR_(max) (KBr) 3422 (br, s), 3101 (w), 1779 (w), 1717,1635 (s), 1488, 1388, 1242, 1162, 1036, 751, 681, and 526. Treatment of1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylic acid with dil. HCl (2.0N) gave the corresponding N-protonated1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylic acid containing freecarboxylic acids. IR_(max) (KBr) 3421 (br, s), 3245, 2930, 2859, 2575(CO₂H), 1723 (s, CO₂H), 1641, 1453, 1414, 1169, 1111 (s), 955 (w), 801,665 (w), 599 (w), and 470.

EXAMPLE 2 Synthesis of E-isomer of1-dimethyl-3-hydroxyphenylmethyl-fulleropyrrolidine-1,3-dicarboxylicAcid

In a conical flask charged with DL-tyrosine (4.52 g, 25 mmol) and amixture of water and ethanol (20 ml, 2: 1) and stirred for a period of20 min was added pyruvic acid (2.2 g, 25 mmol). The reaction mixture wasstirred at 50° C. for 2.0 h under basic condition at pH 810 using NaOHas a titration agent. The resulting yellowish solution was then addedcopper (II) chloride (3.4 g, 25 mmol) in water-ethanol (20 ml) andstirred for an additional 24 h, causing precipitation of pale bluesolids. The solids were filtered, washed with water, ethanol,diethylether, and dried to yield N-pyruvylidenetyrosinatoaquocopper (II)complex. IR_(max) (KBr) 3490, 3371, 3290, 3151, 3052, 2971, 2932, 1613(s), 1580, 1520, 1448, 1408, 1335, 1242, 1123, 1070, 891, 848, 810, 744,705, 600, and 539.

Alternatively, in a conical flask charged with DL-alanine (2.27 g, 25mmol) and a mixture of water and ethanol (20 ml, 2:1) and stirred for aperiod of 20 min was added p-hydroxyphenylpyruvic acid (4.5 g, 25 mmol).The reaction mixture was stirred at ambient temperature for 2.0 h. Theresulting yellowish solution was then added copper (II) acetate (5.0 g,25 mmol) in water-ethanol (20 ml) and stirred for an additional 24 h,causing precipitation of greenish blue solids. The solids were filtered,washed with ethanol, diethylether, and dried to yield blue solids ofN-hydroxyphenylpyruvylidene-alaninatoaquocopper (II) complex. IR_(max)(KBr) 3423, 3255, 2975, 2941, 1621 (s), 1518, 1457, 1396, 1363, 1250,1154, 1122, 859, 848, 792, 778, 715, 678, and 576.

To a solution of C₆₀ (500 mg, 0.69 mmol) in o-dichlorobenzene (150 ml),N-pyruvylidenetyrosinatoaquocopper (II) complex (1.04 g, 3.44 mmol, 5.0equiv.) or N-hydroxyphenylpyruvylidene-alaninatoaquocopper (II) complex(1.35 g, 4.2 mmol, 6.0 equiv.) in pyridine (40 ml) and triethylamine wasadded via syringe in sequence under N₂. The solution mixture was stirredfor a period of 24 h at ambient temperature. Unreacted copper complexpartially suspended in the solution was removed. It was added hexane(100 ml) to effect precipitation of solid products. The solidprecipitates were isolated by centrifuge, washed with hexane (50 ml),and dried in vaccuo. It was further washed twice by water, brine, andCH₃CN (20 ml each) and dried in vaccuo to afford brown solids of1-dimethyl-3-hydroxyphenylmethyl-fulleropyrrolidine-1,3-dicarboxylatoaquocopper(II) complex (665 mg).

Brown solids of1-dimethyl-3-hydroxyphenylmethyl-fulleropyrrolidine-1,3-dicarboxyl-atoaquocopper(II) complex (0.5 g) were dissolved in a mixture of pyridine (25 ml) andwater (25 ml) or o-dichlorobenzene EtOH. It was stirred in the presenceof Dowex acid resin (50WX8, 2.0 g) for a period of 4.0 h. The solidresin was filtered off. The remaining solution was stirred further withfresh Dowex acid resin (50WX8, 1.5 g) for an additional 30 min. At theend of the ion exchanging reaction, Dowex resin was filtered. Aftersolvent evaporation of the filtrate, the resulting dark solids werewashed with ethanol and dried in vaccuo to give the product of1-dimethyl-3-hydroxyphenylmethyl-fulleropyrrolidine-1,3-dicarboxylicacid. IR_(max) (KBr) 3430 (br, s), 2933 (w), 2866, 1659 (s), 1620, 1517,1442, 1364, 1321, 1237, 1175, 1112, 821, and 528. Treatment of1-dimethyl-3-hydroxyphenylmethyl-fulleropyrrolidine-1,3-dicarboxylicacid with dil. HCl (2.0 N) gave the corresponding N-protonated1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylic acid containing freecarboxylic acids. IR_(max) (KBr) 3401 (br, s), 3230, 2933, 2851, 28002500 (br, CO₂H), 1758, 1718, 1646 (s), 1516, 1442, 1363, 1320, 1174,1036, 991, 822, and 504.

EXAMPLE 3 Synthesis of E-isomer of1-dimethyl-3-(3,4-dihydroxyphenyl)methyl-fulleropyrrolidine-1,3-dicarboxylicAcid

In a conical flask charged with 3-(3,4-dihydroxyphenyl)-L-alanine(L-DOPA, 1.0 g, 5.1 mmol) and a mixture of water and ethanol (10 ml,2:1) and stirred for a period of 20 min was added pyruvic acid (446 mg,5.1 mmol). The reaction mixture was stirred at 40° C. for 2.0 h. Theresulting yellowish solution was then added copper (II) acetate (1.0 g,5.1 mmol) in water-ethanol (10 ml) and stirred for an additional 24 h,causing precipitation of pale blue solids. The solids were filtered,washed with water, ethanol, and dried to yieldN-pyruvylidene-3-(3,4-dihydroxyphenyl)alaninatoaquocopper (II) complex(1.02 g). IR_(max) (KBr) 3412 (br, s), 3251 (br, s), 1615 (s), 1500,1382, 1282, 1251, 1157, 869, 721, and 645.

To a solution of C₆₀ (100 mg, 0.14 mmol) in o-dichlorobenzene (40 ml),N-pyruvylidene-3-(3,4-dihydroxyphenyl)alaninatoaquocopper (II) complex(288 mg, 0.84 mmol, 6.0 equiv.) in pyridine (35 ml) was added viasyringe under N₂. The solution mixture was stirred for a period of 15 hat 50-60° C. It was added hexane (100 ml) to effect precipitation ofsolid products. The solid precipitates were isolated by centrifuge,washed with hexane (50 ml), and dried in vaccuo. It was further washedtwice by water, brine, and CH₃CN (20 ml each) and dried in vaccuo toafford dark brown solids of1-dimethyl-3-(3,4-dihydroxyphenyl)methyl-fulleropyrrolidine-1,3-dicarboxylato-aquocopper(II) complex (150 mg).

Brown solids of1-dimethyl-3-(3,4-dihydroxyphenyl)methyl-fulleropyrrolidine-1,3-dicarboxyl-atoaquocopper(II) complex (150 mg) were dissolved in a mixture of pyridine (20 ml)and water (20 ml). It was stirred in the presence of Dowex acid resin(50WX8, 1.0 g) for a period of 2.0 h. The solid resin was filtered off.The remaining solution was stirred further with fresh Dowex acid resin(50WX8, 1.0 g) for an additional 30 min. At the end of the ionexchanging reaction, Dowex resin was filtered. After solvent evaporationof the filtrate, the resulting dark solids were washed with ethanol anddried in vaccuo to give the product of1-dimethyl-3-(3,4-dihydroxyphenyl)methyl-fulleropyrrolidine-1,3-dicarboxylicacid (200 mg). IR_(max) (KBr) 3395 (br, s), 2950 (w), 2922 (w),2800-2500 (br), 1613, 1545, 1470, 1427, 1302, 1187, 1162, 1067 (w), 862,701 (w), 625 (w), and 525.

EXAMPLE 4 Synthesis of E-isomer of fulleropyrrolidine-1,3-di(3-propanoicacid)-1,3-dicarboxylic Acid

In a conical flask charged with L-glutamic acid (1.47 g, 10.0 mmol) anda mixture of water and ethanol (20 ml, 2:1) and stirred for a period of20 min was added 2-ketoglutaric acid (1.46 g, 10.0 mmol). The reactionmixture was stirred at ambient temperature for a period of 2.0 h at pH6.0 7.0 using NaOH as a titrating agent. The resulting colorlesssolution was then added copper (II) acetate (1.99 g, 10.0 mmol) inwater-ethanol (10 ml) and stirred for an additional 2 h, causingprecipitation of pale blue solids. The solids were filtered, washed withethanol and ether, and dried in vaccuo to yieldN-(2-ketoglutarylidene)-L-glutamitoaquocopper (II) complex (2.6 g).IR_(max) (KBr) 3439 (br, s), 3282 (br, s), 2949, 2581, 1623 (s), 1392,1343, 1231, 1147, 1095, 939, 676, and 641.

To a solution of C₆₀ (400 mg, 0.64 mmol) in o-dichlorobenzene (100 ml),N-(2-ketoglutarylidene)-L-glutamitoaquocopper (II) complex (1.3 g, 6.0equiv.) in pyridine (50 ml) was added via syringe under N₂. The solutionmixture was stirred in the presence of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 300 mg) for a period of 5 h atambient temperature. At the end of reaction, hexane (100 ml) was addedto the reaction mixture causing precipitation of solid products. Thesolid precipitates were isolated by centrifuge, washed with hexane (50ml), and dried in vaccuo. It was further washed twice by water, brine,and CH₃CN (20 ml each) and dried in vaccuo to afford dark brown solidsof fulleropyrrolidine-1,3-di(3-propanoicacid)-1,3-dicarboxylato-aquocopper (II) complex. It was then dissolvedin DMSO (30 ml) and treated with Dowex acid resin (50WX8, 1.0 g) for aperiod of 2.0 h. The solid resin was filtered off. The remainingsolution was stirred further with fresh Dowex acid resin (50WX8, 1.0 g)for an additional 30 min. At the end of the ion exchanging reaction,Dowex resin was filtered. Solid products were precipitated from thefiltrate by addition of a mixture of ether and acetone. The precipitateswere washed with ether and acetone and dried in vaccuo to give brownsolids of fulleropyrrolidine-1,3-di(3-propanoic acid)-1,3-dicarboxylicacid (550 mg). IR_(max) (KBr) 3422 (br, s), 2928 (w), 2857 (w), 1716,1635 (s), 1435, 1371, 1200 (w), 1018, 952, and 527. Treatment offulleropyrrolidine-1,3-di(3-propanoic acid)-1,3-dicarboxylic acid withdil. HCl (2.0 N) gave the corresponding N-protonatedfulleropyrrolidine-1,3-di(3-propanoic acid)-1,3-dicarboxylic acidcontaining free carboxylic acids. IR_(max) (KBr) 3433 (br, s), 2928,2853, 2800 2500 (br, C0₂H), 1792 (w), 1721 (s), 1630 (s), 1440, 1411,1328, 1184, 1004, 949, 764, and 526.

EXAMPLE 5 Synthesis of E-isomer of1-methyl-3-thiomethyl-fulleropyrrolidine-1,3-dicarboxylic Acid

In a conical flask charged with L-cysteine (1.21 g, 10.0 mmol) and amixture of water and ethanol (20 ml, 2:1) and stirred for a period of 20min was added pyruvic acid (880 mg, 10.0 mmol). The reaction mixture wasstirred at ambient temperature for a period of 1.0 h. The resultingcolorless solution was then added copper (II) acetate (1.99 g, 10.0mmol) in water-ethanol (10 ml) and stirred for an additional 2 h,causing precipitation of dark gray solids. The solids were filtered,washed with ethanol and ether, and dried in vaccuo to yieldN-pyruvylidene-L-cysteinatoaquocopper (II) complex (1.6 g). IR_(max)(KBr) 3447 (br), 3221 (br), 2994 (w), 2935 (w), 1666, 1625, 1598 (s),1574 (s), 1423, 1404, 1378, 1315, 1178, 1016, 970, 937, 884, 759, 713,and 642.

To a solution of C₆₀ (400 mg, 0.64 mmol) in o-dichlorobenzene (100 ml),N-pyruvylidene-L-cysteinatoaquocopper (II) complex (600 mg, 6.0 equiv.)in pyridine (30 ml) was added via syringe under N₂. The mixture wasstirred for a short period of 10 min at ambient temperature to give asolution containing suspended brown solids. At the end of reaction,hexane (100 ml) was added to effect complete precipitation of solidproducts. The solid precipitates were isolated by centrifuge, washedwith hexane (50 ml), and dried in vaccuo. It was then dissolved in amixture of o-dichlorobenzene and ethanol (1:1, 40 ml) and treated withDowex acid resin (50WX8, 1.0 g) for a period of 2.0 h. The solid resinwas filtered off. The remaining solution was stirred further with freshDowex acid resin (50WX8, 1.0 g) for an additional 30 min. At the end ofthe ion exchanging reaction, Dowex resin was filtered. Ethanol wasremoved from the filtrate and solid products were precipitated byaddition of ether to the remaining liquid. The precipitates were washedwith ether and dried in vaccuo to give brown solids of1-methyl-3-thiomethyl-fulleropyrrolidine-1,3-dicarboxylic acid (520 mg).IR_(max) (KBr) 3429 (br, s), 2979 (w), 2935 (w), 1721, 1631 (s), 1540(w), 1377, 1232, 1180, 955 (w), 767, and 525.

EXAMPLE 6 Synthesis of E-isomer of1-methyl-3-hydroxymethyl-fulleropyrrolidine-1,3-dicarboxylic Acid

In a conical flask charged with L-serine (1.19 g, 10.0 mmol) and amixture of water and ethanol (20 ml, 2:1) and stirred for a period of 20min was added pyruvic acid (880 mg, 10.0 mmol). The reaction mixture wasstirred at ambient temperature for a period of 2.0 h. The resultingcolorless solution was then added copper (II) acetate (1.99 g, 10.0mmol) in water-ethanol (10 ml) and stirred for an additional 2 h,causing precipitation of pale blue solids. The solids were filtered,washed with ethanol and ether, and dried in vaccuo to yieldN-pyruvylidene-L-serinatoaquocopper (II) complex (1.7 g). IR_(max) (KBr)3369 (br, s), 2988 (w), 1731, 1625 (s), 1398, 1341, 1222, 1199, 1145(w), 1106, 1073, 957 (w), 894, 857, 723, 648, and 589.

To a solution of C₆₀ (400 mg, 0.64 mmol) in o-dichlorobenzene (100 ml),N-pyruvylidene-L-serinatoaquocopper (II) complex (590 mg, 6.0 equiv.) inpyridine (30 ml) was added via syringe under N₂. The mixture was stirredin the presence of triethylamine for a period of 12 h at ambienttemperature to give a solution containing suspended brown solids. At theend of reaction, hexane (100 ml) was added to effect completeprecipitation of solid products. The solid precipitates were isolated bycentrifuge, washed with hexane (50 ml), and dried in vaccuo. It was thendissolved in a mixture of o-dichlorobenzene and ethanol (1:1, 40 ml) andtreated with Dowex acid resin (50WX8, 1.0 g) for a period of 2.0 h. Thesolid resin was filtered off. The remaining solution was stirred furtherwith fresh Dowex acid resin (50WX8, 1.0 g) for an additional 30 min. Atthe end of the ion exchanging reaction, Dowex resin was filtered.Ethanol was removed from the filtrate and solid products wereprecipitated by addition of ether to the remaining liquid. Theprecipitates were washed with ether and dried in vaccuo to give brownsolids of 1-methyl-3-hydroxymethyl-fulleropyrrolidine-1,3-dicarboxylicacid (500 mg). IR_(max) (KBr) 3445 (br, s), 2926 (w), 2853 (w), 1786,1729, 1633 (s), 1454 (w), 1381, 1168, 1107, 1076, 1042, and 533.Treatment of1-methyl-3-hydroxymethyl-fulleropyrrolidine-1,3-dicarboxylic acid withdil. HCl (2.0 N) gave the corresponding N-protonated1-methyl-3-hydroxymethyl-fulleropyrrolidine-1,3-dicarboxylic acidcontaining free carboxylic acids. IR_(max) (KBr) 3421 (br, s), 3211,2954, 2800 2500 (br, CO₂H), 1762, 1719 (CO₂H), 1630 (s), 1428 (w), 1380,1183, 1112 (w), 1036, 991, 928 (w), 755 (w), 625 (w), and 526.

EXAMPLE 7 Synthesis of E-isomer of1-isobutyl-3-(o-hydroxyphenyl)-fulleropyrrolidine-1-carboxylic Acid

In a conical flask charged with L-leucine (2.44 g, 20.0 mmol) and amixture of water and ethanol (20 ml, 2:1) and stirred for a period of 20min was added salicylaldehyde (2.62 g, 20.0 mmol). The reaction mixturewas stirred at 50° C. for a period of 5.0 h at pH 7.0 using NaOH as atitrating agent. The resulting pale yellow solution was then addedcopper (II) acetate (4.0 g, 20.0 mmol) in water-ethanol (10 ml) andstirred for an additional 30 min, causing precipitation of paleblue-green solids. The solids were filtered, washed with ethanol andether, and dried in vaccuo to yieldN-(2-hydroxybenzylidene)-L-leucinatoaquocopper (II) complex (4.5 g).IR_(max) (KBr) 3383 (br, w), 3322 (br, w), 3252 (br, w), 2961, 2912,2875, 1649 (s), 1628, 1606, 1528, 1451, 1336, 1198, 1147, 1079 (w), 861(w), 802, 767, 730, and 564.

To a solution of C₆₀ (1.0 g, 1.3 mmol) in o-dichlorobenzene (300 ml),N-(2-hydroxybenzylidene)-L-leucinatoaquocopper (II) complex (1.64 g, 5.2mmol, 4.0 equiv.) in pyridine (100 ml) was added via syringe under N₂.The mixture was stirred in the presence of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.0 g) for a period of 15 h atambient temperature to give a solution containing suspended brownsolids. At the end of reaction, hexane (100 ml) was added to effectcomplete precipitation of solid products. The solid precipitates wereisolated by centrifuge, washed with hexane (50 ml), and dried in vaccuo,yielding 1.4 g of products. It was then dissolved in a mixture oftoluene and ethanol (9:1, 100 ml, brown solution) and treated with Dowexacid resin (50WX8, 2.0 g) for a period of 2.0 4.0 h. The solid resin wasfiltered off. The remaining solution was stirred further with freshDowex acid resin (50WX8, 1.5 g) for an additional 30 min. At the end ofthe ion exchanging reaction, Dowex resin was filtered. Solvent wasremoved from the filtrate and resulting solid products were washed withhexane and dried in vaccuo to give brown solids of1-isobutyl-3-(o-hydroxyphenyl)-fulleropyrrolidine-1-carboxylic acid (900mg). R_(f) 0.35 (thin layer chromatography, SiO₂, toluene-ethanol/9:1);IR_(max) (KBr) 3440 (br, s), 2957, 2929, 2866, 1706, 1619, 1575, 1495(w), 1446, 1387 (w), 1293 (w), 1252, 1228, 1179, 1155, 1043, and 650;m/z 955 (M⁺).

EXAMPLE 8 Synthesis of E-isomer of1-methyl-3-ethyl-3′-(o-hydroxyphenyl)-fulleropyrrolidine-1-carboxylicAcid

Into a conical flask charged with L-alanine (1.78 g, 20.0 mmol),molecular sieves (4 Å), and ethanol (20 ml) was added2-hydroxypropiophenone (3.0 g, 20.0 mmol). The reaction mixture wasstirred at the reflux temperature for a period of 24.0 h at pH 8.0 usingNaOH as a titrating agent. The resulting yellow solution was then addedcopper (II) acetate (4.0 g, 20.0 mmol) in water-ethanol (15 ml, 2:1) andstirred for an additional 2.0 h, causing precipitation of green solids.The solids were filtered, washed with ethanol and ether, and dried invaccuo to yield N-(2-hydroxypropiophenonylidene)-L-alainatoaquocopper(II) complex (4.0 g). IR_(max) (KBr) 3470 (br, w), 3305, 3245, 2981,2933, 2880, 1622 (s), 1575, 1465, 1401, 1363, 1298, 1142, 1125, 1076,1028, 928, 857, 788, 709, 672, 618, and 575.

To a solution of C₆₀ (300 mg, 0.4 mmol) in o-dichlorobenzene (100 ml),N-(2-hydroxypropiophenonylidene)-L-alainatoaquocopper (II) complex (590mg, 1.8 mmol, 4.5 equiv.) in pyridine (30 ml) was added via syringeunder N₂. The mixture was stirred in the presence of triethylamine (0.5ml) for a period of 24 h at ambient temperature to give a solutioncontaining suspended brown solids. At the end of reaction, hexane (50ml) was added to effect complete precipitation of solid products. Thesolid precipitates were isolated by centrifuge, washed with hexane (30ml), and dried in vaccuo. It was then dissolved in a mixture ofo-dichlorobenzene and ethanol (1:1, 40 ml) and treated with Dowex acidresin (50WX8, 1.0 g) for a period of 2.0 h. The solid resin was filteredoff. The remaining solution was stirred further with fresh Dowex acidresin (50WX8, 1.0 g) for an additional 30 min. At the end of the ionexchanging reaction, Dowex resin was filtered. Solvent was removed fromthe filtrate and resulting solid products were washed with hexane CH₃CNand dried in vaccuo to give brown solids of1-methyl-3-ethyl-3′-(o-hydroxyphenyl)-fulleropyrrolidine-1-carboxylicacid (310 mg). IR_(max) (KBr) 3435 (br, s), 3089, 2933, 1722 (w), 1625(s), 1520 (w), 1413, 1364, 1308, 1168, 1118 (s), 1037 (s), 1010 (s),677, and 528. Treatment of1-methyl-3-ethyl-3′-(o-hydroxyphenyl)-fulleropyrrolidine-1-carboxylicacid with dil. HCl (2.0 N) gave the corresponding N-protonatedderivative containing free carboxylic acids. IR_(max) (KBr) 3427 (br,s), 2950, 2800-2500 (br, CO₂H), 1726 (CO₂H), 1637 (s), 1514, 1418 (w),1258 (w), 1205, 1119, 1038, and 612.

EXAMPLE 9 Synthesis of E-isomer of1-methyl-3-(2,3,4-trihydroxyphenyl)-fulleropyrrolidine-1-carboxylic Acid

In a conical flask charged with L-alanine (0.98 g, 10.0 mmol) and amixture of water and ethanol (20 ml, 2:1) and stirred for a period of 10min was added 2.3.4-trihydroxybenzaldehyde (1.54 g, 10.0 mmol). Thereaction mixture was stirred at 40° C. for a period of 2.0 h. Theresulting yellow solution was then added copper (II) acetate (2.0 g,10.0 mmol) in water-ethanol (5.0 ml) and stirred for an additional 30min, causing precipitation of dark green solids. The solids werefiltered, washed with ethanol and ether, and dried in vaccuo to yieldN-(2.3.4-trihydroxybenzylidene)-L-alainnatoaquocopper (II) complex (1.95g). IR_(max) (KBr) 3322 (br), 3248 (br), 2919, 2853, 1574 (s), 1484,1443, 1399, 1320, 1278, 1187 (w), 1098, 1041 (w), 791, 731, 671, and519.

To a solution of C₆₀ (300 mg, 0.4 mmol) in o-dichlorobenzene (100 ml),N-(2.3.4-trihydroxybenzylidene)-L-alainnatoaquocopper (II) complex (630mg, 2.0 mmol, 5.0 equiv.) in pyridine (30 ml) was added via syringeunder N₂. The mixture was stirred for a period of 15 h at ambienttemperature to give a solution containing suspended brown solids. At theend of reaction, hexane (50 ml) was added to effect completeprecipitation of solid products. The solid precipitates were isolated bycentrifuge, washed with hexane (30 ml), and dried in vaccuo. It was thendissolved in a mixture of o-dichlorobenzene and ethanol (1:1, 40 ml) andtreated with Dowex acid resin (50WX8, 1.0 g) for a period of 2.0 h. Thesolid resin was filtered off. The remaining solution was stirred furtherwith fresh Dowex acid resin (50WX8, 1.0 g) for an additional 30 min. Atthe end of the ion exchanging reaction, Dowex resin was filtered.Solvent was removed from the filtrate and solids were precipitated byaddition of diethylether. The solid precipitates were washed with hexaneand dried in vaccuo to give brown solids of1-methyl-3-(2,3,4-trihydroxyphenyl)-fulleropyrrolidine-1-carboxylic acid(290 mg). IR_(max) (KBr) 3422 (br, s), 2972, 2927, 2846, 1706 (w), 1635(s), 1447, 1374, 1314, 1162, 1013, 951, and 526. Treatment of1-methyl-3-(2,3,4-trihydroxyphenyl)-fulleropyrrolidine-1-carboxylic acidwith dil. HCl (2.0 N) gave the corresponding N-protonated derivativecontaining free carboxylic acids. IR_(max) (KBr) 3420 (br, s), 3245(br), 2978 (w), 2932 (w), 2857 (w), 2800-2500 (br, C0₂H), 1709 (CO₂H),1636 (s), 1448, 1178, 1129, 1037, 1011, 952, and 527.

EXAMPLE 10 Synthesis of1,3-dimethyl-N-p-bromobenzyl)fulleropyrrolidine-1,3-dicarboxylicAnhydride

To a solution of 1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylic acid(220 mg, 0.25 mmol) in a mixture of o-dichlorobenzene and DMSO (6:1, 50ml), phosphorous pentaoxide (250 mg) was added under N₂. The mixture wasstirred at 50° C. for a period of 12.0 h to effect dehydrative anhydrideformation. At the end of reaction, the insoluble solids were separatedby centrifuge. The remaining solution was transferred via syringe intothe second reaction flask containing p-bromobenzyl chloride (66 mg, 0.3mmol) and triethylamine (0.1 ml). The mixture was stirred at 50° C. foran additional 8.0 h under N₂. Diethyl ether (50 ml) was then added toeffect complete precipitation of solid products. The solid precipitateswere isolated by centrifuge, washed with diethyl ether (30 ml), water,ethanol, and diethyl ether in sequence and dried in vacuo to give brownsolids of1,3-dimethyl-N-p-bromobenzyl)fulleropyrrolidine-1,3-dicarboxylicanhydride (180 mg). ¹H NMR (two amide isomers in an equal amount) 1.14(s, 6H), 1.24 (s, 6H), 7.75 (dd, 4H), 8.15 (dd, 4H); IR_(max) (KBr) 3402(br, s), 2984, 2925, 1787 (w), 1737 (s), 1630, 1591, 1513 (w), 1399,1255, 1173, 1094, 1071, 1008, 751, and 527.

EXAMPLE 11 Synthesis ofoligo[1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylic N-amide]

To a solution of 1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylic acid(220 mg, 0.25 mmol) in a mixture of o-dichlorobenzene and DMSO (6:1, 50ml), phosphorous pentaoxide (250 mg) was added under N₂. The mixture wasstirred at 50° C. for a period of 12.0 h to effect dehydrative anhydrideformation. At the end of reaction, the insoluble solids were separatedby centrifuge. The remaining solution was transferred via syringe underN₂ into the second reaction flask containing1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.0 g). The mixture was stirredat 100° C. for an additional 24.0 h under N₂ to afford a darkbrown-black solution. Diethyl ether (50 ml) was then added to effectcomplete precipitation of solid products. The solid precipitates wereisolated by centrifuge, washed twice with diethyl ether (30 ml),ethanol, and diethyl ether in sequence. It was treated with dil HCl (2N) in THF, washed with THF, and dried in vaccuo, to give dark brownsolids of oligo[1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylicN-amide] (165 mg). IR_(max) (KBr) 3402 (br, s), 2931, 2861, 1712 (w),1661 (s), 1613, 1442, 1372, 1324, 1156 (s), 1036 (s), 990, 675, and 611.

EXAMPLE 12 Synthesis of1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylic Acid,C₆₀[C(CH₃)CO₂H]₂NCO—CH₂CH₂CO₂H

To a solution of 1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylic acid(440 mg, 0.5 mmol) in a mixture of o-dichlorobenzene and DMSO (6:1, 80ml), succinic anhydride (100 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU, 1.0 g) were added under N₂. The mixture was stirred at 30° C. fora period of 4.0 h. At the end of reaction, the solution was treated withdil. HCl (2.0 N). Diethyl ether (50 ml) was then added to effectcomplete precipitation of solid products. The solid precipitates wereisolated by centrifuge, washed twice with diethyl ether (30 ml), water,and diethyl ether in sequence and dried in vaccuo, to give dark brownsolids of 1 ,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylicacid (480 mg). IR_(max) (KBr) 3426 (br, s), 2930, 2595 (br, CO₂H), 1752(w), 1718 (s, CO₂H), 1626, 1402, 1180, 1086, 1000, 773 (w), 653 (w), and525 (w).

EXAMPLE 13 Synthesis oftris(hexadecaanilino)-1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylate,C₆₀[C(CH₃)CO—(NH—C₆H₄—N═C₆H₄═N—C₆H₄—NH—C₆H₄—)₄—H]₂NCO—CH₂CH₂CO—(NH—C₆H₄—N═C₆H₄═N—C₆H₄—NH—C₆H₄—)₄—H

To a solution of1,3-dimethyl-N-succinamito-fulleropyrrolidine-1,3-dicarboxylic acid,C₆₀[C(CH₃)CO₂H]₂NCO—CH₂CH₂CO₂H, (498 mg, 0.5 mmol) in a mixture ofo-dichlorobenzene and DMSO (6:1, 100 ml), hexadecaaniline (emeraldinebase form, 2.2 g, 1.5 mmol), 1,3-dicyclohexylcarbodiimide (DCC, 340 mg,1.65 mmol), and 1-hydroxybenzotriazole (BtOH, 223 mg, 1.65 mmol) wereadded under N₂. The mixture was stirred at 40° C. for a period of 24.0h. At the end of reaction, the solution was added diethyl ether (100 ml)to effect complete precipitation of solid products. The solidprecipitates were isolated by centrifuge, treated with aqueous NH₄OH,washed twice with water and diethyl ether and dried in vaccuo. to givedark blue solids oftris(hexadecaanilino)-1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylate(2.5 g). IR_(max) (KBr) 3433 (br, s), 3284, 2932 (w), 2859 (w), 1596,1506 (s), 1305, 1252, 1150, 822, 749, 696, and 506.

EXAMPLE 14 Synthesis oftris(glycylglycyl)-1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylate,C₆₀[C(CH₃)CO—(NHCH₂CO—NHCH₂CO₂H]₂NCO—CH₂CH₂CO—NHCH₂CO—NHCH₂CO₂H

To a solution of1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylic acid,C₆₀[C(CH₃)CO₂H]₂NCO—CH₂CH₂CO₂H, (498 0.5 mmol) in a mixture ofo-dichlorobenzene and DMSO (6:1, 100 ml), glycylglycine (198 mg, 1.5mmol), 1,3-dicyclohexylcarbodiimide (DCC, 340 mg, 1.65 mmol), and1-hydroxybenzotriazole (BtOH, 223 mg, 1.65 mmol) were added under N₂.The mixture was stirred at 40° C. for a period of 24.0 h. At the end ofreaction, the solution was added diethyl ether (100 ml) to effectcomplete precipitation of solid products. The solid precipitates wereisolated by centrifuge, treated with dil. HCl (2.0 N), washed twice withwater and diethyl ether and dried in vaccuo. to give dark brown solidsoftris(glycylglycyl)-1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylate(480 mg). IR_(max) (KBr) 3431 (br, s), 2929, 2860 (w), 1773, 1701, 1654(s), 1550, 1391, 1227, 1178, 1056 (w), 999 (w), and 527.

EXAMPLE 15 Detection of High Free Radical Scavenging Potency ofHydrophilic Fullerene Derivatives

The xanthine/xanthine oxidase enzymatic system is highly effective forthe production of superoxide radicals (O₂). Reaction of superoxideradicals with cytochrome (Fe⁺³) C may result in a product of reducedcytochrome (Fe⁺²) C which shows a respectable optical absorption at 550nm. Therefore, the detected optical absorption intensity of the reducedcytochrome (Fe⁺²) C can be correlated to the quantity of superoxideradicals reacted with cytochrome (Fe⁺³) C. Scavenging of superoxideradicals by hydrophilic fullerene derivatives in the bio-medium inhibitsthe formation of reduced cytochrome (Fe⁺²) C and thus reduce the opticalabsorption at 550 nm.

In one experiment, xanthine (50 M) was added to a physiological medium(3 ml) containing cytochrome C (10 M), ethylenediaminetetraacetic acid(EDTA) (10 mM) and a phosphate buffer (50 mM) at pH 7.8. The mixture wasthen added xanthine oxidase in quantity enough to induce 0.025 unit ofoptical absorption at 550 nm per 5 min (Mc Cord, et al. J. Biol. Chem.1969, 244, 6049.). Subsequently,1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylic acid,C₆₀[C(CH₃)CO₂H]₂NCO—CH₂CH₂CO₂H, prepared in Example 12, in aconcentration of 0, 5.0, 10.0, 25.0, 50, and 100 M was added inseparated runs while the absorption intensity of the reduced cytochromeC was recorded. A rapid decrease of reduced cytochrome C to roughly 50%and 20% of the control value was obtained with the dose of1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylic acid as 25and 100 M, respectively. These results substantiated efficientscavenging of superoxide radicals by1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylic acid thatled to the inhibition of cytochrome C reduction.

EXAMPLE 16

The growth inhibitory effect of1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylic acid,C₆₀[C(CH₃)CO₂H]₂NCO—CH₂CH₂CO₂H, which was prepared as described inExample 12, on fibrosarcoma tumor cells upon photo-irradiation wasstudied in vitro. Fibrosarcoma tumor cells (0.5 ml, 4×10⁴/ml, CCRC60037) were grown in the MEM medium in a 24-well plate for a period of24 h. It was treated by1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylic acid in aconcentration of 0.0, 2.5, 5.0, 7.5, and 10.0 M for a period of 24hours. The MEM medium was removed and replaced by the fresh medium (1.0ml). The cell-containing plates were exposed to a fluorescence lightsource (27 W) in a distance of 5-6 cm for a period of 10, 20, 40, and 60min. The plates were then kept in incubator at 37° C. a period of 48 h.Measurement of cell viability in each plate was performed by the MTTassay using optical absorption at 540 nm. The data indicated a rapiddecrease in the tumor cell count under application of1,3-dimethyl-N-succinamitofulleropyrrolidine-1,3-dicarboxylic acid in aconcentration of only 2.5 M with a photo-irradiation period of more than20 min. These results substantiated high efficacy of the growthinhibition on fibrosarcoma tumor cells upon photo-irradiation.

Other Embodiments

From the above description, one skilled in the art can easily ascertainthe essential characteristics of the present invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. Thus, other embodiments are also within the claims.

What is claimed is:
 1. A compound of formula (VII):

wherein F₁ is F(—K)_(m)(—Y—Z)_(q) in which F is a fullerene core; eachK, independently, is —OH, —SH, —NH₂, —NHOH, —SO₃H, —OSO₃H, —CO₂H,—CONH₂, —CONHNH₂, —P(OH)₃, —PO(OH)₂, —O—PO(OH)₂, —O—PO(OH)—O—PO(OH)₂,—O—PO(O⁻)—O—CH₂CH₂—NH₃ ⁺, —O—PO(O⁻)—O—CH₂CH₂—N⁺(CH₃)₃, -glycoside,—OCH₃, —OCH₂(CHOH)₄—CH₂OH, —OCH₂(CHOH)₂—CH₂OH, —NH—CH₂—CO₂H,—[CH(CO₂H)—CH₂]₁₋₁₀₀—OH, —[CH(CO₂R^(a))—CH₂]₁₋₁₀₀—OH,—[C(CH₃)(CO₂R^(a))—CH₂]₁₋₁₀₀—OH, —[C(CH₃)(CO₂ R^(a))—CH₂]₁₋₁₀₀—OH,—N(OH)₂, —NH₃ ⁺, —N⁺H₂R^(a), —N⁺HR^(a)R^(b), or —N⁺R^(a)R^(b)R^(c); eachY is —A—B—, in which A is —O—, —NH—, —S—, —CO—O—, —O—CO—, —O—CO—O—,—CO—NH—, NH—CO—NH—, —CO—NH—, or —NH—CO—; and B is—R^(a)—O—[Si(CH₃)₂—O—]₁₋₁₀₀, C₁₋₂₀₀₀ alkyl, C₆₋₄₀ aryl, C₇₋₂₀₀₀alkylaryl, C₇₋₂₀₀₀ arylalkyl, (C₁₋₃₀ alkyl ether)₁₋₁₀₀, (C₆₋₄₀ arylether)₁₋₁₀₀, (C₇₋₂₀₀₀ alkylaryl ether)₁₋₁₀₀, (C₇₋₂₀₀₀ arylalkylether),₁₋₁₀₀, (C₁₋₃₀ alkyl thioether)₁₋₁₀₀, (C₆₋₄₀ aryl thioether)₁₋₁₀₀,(C₇₋₂₀₀₀ alkylaryl thioether)₁₋₁₀₀, (C₇₋₂₀₀₀ arylalkyl thioether)₁₋₁₀₀,(C₂₋₅₀ alkyl ester)₁₋₁₀₀, (C₇₋₂₀₀₀ aryl ester)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylarylester)₁₋₁₀₀, (C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀, —R^(a)—CO—O—(C₁₋₃₀ alkylether)₁₋₁₀₀, —R^(a)—CO—O—(C₆₋₄₀ aryl ether)₁₋₁₀₀, —R^(a)—CO—O—(C₇₋₂₀₀₀alkylaryl ether)₁₋₁₀₀, —R^(a)—CO—O—(C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀,(C₄₋₅₀ alkyl urethane)₁₋₁₀₀, (C₁₄₋₆₀ aryl urethane)₁₋₁₀₀, (C₁₀₋₂₀₀₀alkylaryl urethane)₁₋₁₀₀, (C₁₀₋₂₀₀₀ arylalkyl urethane)₁₋₁₀₀, (C₅₋₅₀alkyl urea)₁₋₁₀₀, (C₁₄₋₆₀ aryl urea)₁₋₁₀₀, (C₁₀₋₂₀₀₀ alkylarylurea)₁₋₁₀₀, (C₁₀₋₂₀₀₀ arylalkyl urea)₁₋₁₀₀, (C₂₋₅₀ alkyl amide)₁₋₁₀₀,(C₇₋₆₀ aryl amide)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylaryl amide)₁₋₁₀₀, (C₈₋₂₀₀₀arylalkyl amide)₁₋₁₀₀, (C₃₋₃₀ alkyl anhydride)₁₋₁₀₀, (C₈₋₅₀ arylanhydride)₁₋₁₀₀, (C₉₋₂₀₀₀ alkylaryl anhydride)₁₋₁₀₀, (C₉₋₂₀₀₀ arylalkylanhydride)₁₋₁₀₀, (C₂₋₃₀ alkyl carbonate)₁₋₁₀₀, (C₇₋₅₀ arylcarbonate)₁₋₁₀₀, (C₈₋₂₀₀₀ alkylaryl carbonate)₁₋₁₀₀, (C₈₋₂₀₀₀ arylalkylcarbonate)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀ alkylaryl ether, or C₇₋₂₀₀₀arylalkyl ether)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀ aryl ester, C₈₋₂₀₀₀alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀, —R^(a)—O—CO—NH—(R^(b)or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀alkylaryl ether, or C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—, —R^(a)—O—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀ aryl ester, C₈₋₂₀₀₀alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀—R^(c)—O—CO—NH—(R^(b)or Ar—R^(b)—Ar)—NH—CO—O—, R^(a)—NH—CO—NH—(R^(b) orAr—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀ aryl ether, C₇₋₂₀₀₀alkylaryl ether, or C₇₋₂₀₀₀ arylalkyl ether)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀aryl ester, C₈₋₂₀₀₀ alkylaryl ester, or C₈₋₂₀₀₀ arylalkyl ester)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₁₋₃₀ alkyl ether, C₆₋₄₀aryl ether, C₇₋₂₀₀₀ alkylaryl ether, or C₇₋₂₀₀₀ arylakylether)₁₋₁₀₀—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—(C₂₋₅₀ alkyl ester, C₇₋₆₀aryl ester, C₈₋₂₀₀₀ alkylaryl ester; or C₈₋₂₀₀₀ arylalkylester)₁₋₁₀₀—R^(c)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—O—,—R^(a)—O—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—NH—(C₂₋₅₀ alkyl amide, C₇₋₆₀aryl amide, C₈₋₂₀₀₀ alkylaryl amide, or C₈₋₂₀₀₀ arylalkyl amide)₁₋₁₀₀,—R^(a)—NH—CO—NH—(R^(b) or Ar—R^(b)—Ar)—NH—CO—NH—(C₂₋₅₀ alkyl amide,C₇₋₆₀ aryl amide, C₈₋₂₀₀₀ alkylaryl amide, or C₈₋₂₀₀₀ arylalkylamide)₁₋₁₀₀, or a bond; each Z, independently, is —G—D, wherein G is—R^(a)—, —R^(a)—Ar—, —Ar—R^(a)—, or —Ar—; and D is —H, —OH, —SH, —NH₂,—NHOH, —SO₃H, —OSO₃H, —CO₂H, —CONH₂, —CONHNH₂, —CH(NH₂)—CO₂H,—NH—CH₂—CO₂H, —P(OH)₃, —PO(OH)₂, —O—PO(OH)₂, —O—PO(OH)—O—PO(OH)₂,—O—PO(O⁻)—O—CH₂CH₂NH₃ ⁺, —O—PO(O⁻)—O—CH₂CH₂—N⁺(CH₃)₃, -glycoside,-oligosaccharide, —CO-glycoside, —CO-oligosaccharide, —OCH₃,—OCH₂(CHOH)₄—CH₂OH, —OCH₂(CHOH)₂—CH₂OH, —CO—OCH₂(CHOH)₄—CH₂OH,—C₆H₃(OH)₂, —N(CH₂CO₂H)₂, —CO—N(CH₂CO₂H)₂, —CO—NH—C(CH₂CH₂CO₂H)₃,—CO—NH—C(CH₂CH₂OH)₃, —[CH₂—CH(CO₂R^(a))]₁₋₁₀₀—H, —NH₃ ⁺, —N⁺H₂R^(a),—N⁺HR^(a)R^(b), or —N⁺R^(a)R^(b)R^(c), each of R^(a), R^(b), and R^(c),independently, being C₁₋₂₀ alkyl and Ar being aryl; q is 0-30; and m is0-30; provided that the sum of q and m is 0-30; R¹ is ═O; R⁴ is ═O orC₁₋₂₀ hydrocarbon; and each of R² and R⁵, independently, is C₁₋₂₀hydrocarbon; wherein R¹ and R², or R⁴ and R⁵ can join together to formC₆₋₄₀ aryl which is optionally substituted with halide, —H, —HNH₂,—NH₂OH, —NH—CH₂—CO₂H, —CH₂—CH₂—D, —CH₂—B—Z, —CO—CH₂—D, —CO—B—Z, —O—B—Z,or —NH—B—Z; each of B, D, and Z having been defined above; each of R³and R⁶, independently, is —H, —CH₂—D, —B—Z, —G—E, —G—CO—E or a sidechain of an amino acid; each of B, D, and Z having been defined above,and E being E₁, E₂, or E₃, in which E₁ is Y₁,Y₂-amino,(Y₁,Y₂-alkyl)-amino, Y₁,Y₂-ethylenediamino, (dihydroxymethyl)alkylamino,(X₁,X₃-aryl)amino, or X₁,X₃-aryloxy; E₂ is Y₁,Y₂-alkoxy,(Y₁,Y₂-amino)alkoxy, (Y₁,Y₂,Y₃-aryl)oxy, (dihydroxyalkyl)-aryloxy,(Y₁,Y₂,Y₃-alkyl)amino, (Y₁,Y₂,Y₃-aryl)amino, dihydroxyalkylamino,Y₁,Y₂,Y₃-alkoxy, (trihydroxyalkyl)alkoxy, (trihydroxyalkyl)alkylamino,(dicarboxyalkyl)amino, (Y₁,Y₂,Y₃-alkyl)thio, (X₁,X₃-aryl)thio,(Y₁,Y₂-alkyl)thio, (dihydroxyalkyl)thio, Y₁,Y₂-dioxoalkyl, ortri-(Y₁,Y₂,Y₃-methylaminocarboxyethyl)methylamino; and E₃ is((glycosidyl)oxoheteroaryl)amino, ((glycosidyl)oxoaryl)amino,(X₁,X₂,X₃-heteroaryl)amino, (X₁-diarylketone)amino, (X,X₁-oxoaryl)amino,(X,X₁-dioxoaryl)amino, (Y₁-alkyl,Y₂-alkyldioxoheteroaryl)amino,(Y₁-alkyl,Y₂-alkyldioxoaryl)amino,(di(Y₁,Y₂-methyl)dioxoheteroaryl)amino,(di(Y₁,Y₂-methyl)dioxoaryl)amino, ((glycosidyl)heteroaryl)amino,((glycosidyl)aryl)amino, ((carboxylacetylalkyl)oxo-heteroaryl)amino,((carboxylacetylalkyl)oxoaryl)amino,((isopropylaminohydroxy-alkoxy)aryl)arnino, (X₁,X₂,X₃-alkylaryl)amino,(X₁,X₂,X₃-heteroaryl)oxy, (isopropylaminohydroxyalkyl)aryloxy,(X₁,X₂,X₃-oxoheteroaryl)oxy, (X₁,X₂,X₃-oxoaryl)oxy,(X₁,Y₁-oxoheteroaryl)oxy, (X₁-diarylketone)oxy, (X,X₁-oxoaryl)oxy,(X₁,X₂-dioxoaryl)oxy, (Y₁,Y₂,di-aminodihydroxy)alkyl,(X₁,X₂-heteroaryl)thio, ((tricarboxylalkyl)ethylene-diamino)alkoxy,(X₁,X₂-oxoaryl)thio, (X₁,X₂-dioxoaryl)thio, (glycosidylheteroaryl)thio,(glycosidylaryl)thio, Y₁-alkyl(thiocarbonyl)thio,Y₁,Y₂,-alkyl(thiocarbonyl)thio, Y₁,Y₂,Y₃-alkyl(thiocarbonyl)thio,(Y₁,Y₂-aminothiocarbonyl)thio, (pyranosyl)thio, cysteinyl, tyrosinyl,(phenylalainyl)amino, (dicarboxyalkyl)thio, (aminoaryl)₁₋₁₀₀amino,(pyranosyl)amino, (Y₁-aminoaryl)₁₋₁₀₀amino,(amino(sulfoaryl))₁₋₁₀₀amino, peptidyl, thymidinyl, uridinyl,guanosinyl, adenosinyl, cholesteryl, or biotinylalkoxy; wherein X ishalide; each of X₁, X₂, and X₃, independently, is —Y₁, —O—Y₁, —S—Y₁,—NH—Y₁, —CO—O—Y₁, —O—CO—Y₁, —CO—NH—Y₁, —CO—NY₁Y₂, —NH—CO—Y₁, —SO₂—Y₁,—CHY₁Y₂, or —NY₁Y₂; and each of Y₁, Y₂, and Y₃, independently, is —Z or—B—Z; B and Z having been defined above; R⁷ is —R^(d) wherein R^(d) is—OH, —OM, —NNNH₂, —NHOH, —NH—CH₂—CO₂H, —O—B—Z, —NH—B—Z, —E, —O—G—E,—NH—G—E, —O—G—CO—E, or —NH—G—CO—E; M being Cu, Mn, Fe, Co, Ni, Ru, Rh,Os, Zn, Cr, Ti, or Zr ion; and R^(e) is —H, —CH₂—CH₂—D, —CH₂—B—Z,—CH₂—G—E, —CH₂—G—CO—E, —CO—CH₂—D, —CO—B—Z, —CO—G—E, or —CO—G—CO—E; eachof B, D, E, G, and Z having been defined above; R⁸ is R^(e); R⁹ is —O—or a bond; R¹⁰ is —R^(d) or —R^(e); each of which having been definedabove; x is 0, and y is 0 or 1; and p is 2-30; provided that when y is0, R⁴ is ═O, and R⁹ is a bond, and R¹⁰ is —R^(d); that when x is 1, R¹and R² join together to form C₆₋₄₀ aryl, and R⁷ is —O—R^(e); and thatwhen y is 1, R⁴ and R⁵ join together to form C₆₋₄₀ aryl, R⁹ is —O—, andR¹⁰ is —R^(e); or a salt thereof.
 2. The compound of claim 1, wherein Fis C₆₀, C₆₁, C₆₂, C₆₃, C₆₄, C₆₅, C₇₀, C₇₆, C₇₈, C₈₂, C₈₄, or C₉₂, orLa@C_(n), Ho@C_(n), Gd@C_(n), or Er@C_(n), in which n is 60, 74, or 82.3. The compound of claim 1, wherein the sum of q and m is 0-20.
 4. Thecompound of claim 1, wherein p is 2-10.
 5. The compound of claim 1,wherein each of R³ and R⁶, independently, is —H, —B—Z, —G—E, —G—CO—E ora side chain of an amino acid.
 6. The compound of claim 1, wherein R^(d)is —OH, —NHNH₂, —E, —O—G—E, —NH—G—E, —O—G—CO—E, or —NH—G—CO—E.
 7. Thecompound of claim 1, wherein R^(e) is —H, —CH₂—G—E, —CH₂—G—CO—E,—CO—G—E, or —CO—G—CO—E.
 8. The compound of claim 1, wherein y is
 0. 9.The compound of claim 8, wherein R^(d) is —OH, —NHNH₂, —E, —O—G—E,—NH—G—E, —O—G—CO—E, or —NH—G—CO—E.
 10. The compound of claim 9, whereinR^(e) is —H, —CH₂—G—E, —CH₂—G—CO—E, —CO—G—E, or —CO—G—CO—E.
 11. Thecompound of claim 10, wherein p is 2-10.
 12. The compound of claim 1,said compound is oligo(1,3-dimethyl-fulleropyrrolidine-1,3-dicarboxylicN-amide).